Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C@H:3]([C@@H:6]([C@@H:9]([CH2:11][O:12][CH3:13])[OH:10])[O:7][CH3:8])[CH:4]=[O:5].O.[NH2:15][NH2:16]>CO>[NH:15]([C:4]([C@@H:3]([C@@H:6]([C@@H:9]([CH2:11][O:12][CH3:13])[OH:10])[O:7][CH3:8])[O:2][CH3:1])=[O:5])[NH2:16]
Reactant: COC[C@@H](O)[C@@H](OC)[C@H](C=O)OC
Reactant: NN
Solvent: O
Solvent: CO
Product: COC[C@@H](O)[C@@H](OC)[C@@H](OC)C(=O)NN
Reaction time: 48 h

Procedure:
1.7 g (8.5 mmoles) of 2,3,5-tri-O-methyl-D-ribose are dissolved in 5 ml of absolute methanol. While stirring, 4.25 g (85 mmoles) of 100% hydrazine hydrate (dissolved in 5 ml of absolute methanol) are added. As a result slight heating occurs. Stirring is carried out for 2 days of room temperature. Following this methanol and superfluous hydrazine hydrate are removed in a rotary evaporator at room temperature (oil pump vacuum). Following this drying is carried out for one day under oil pump vacuum. A colorless oil is obtained. Yield: 1.6 g (92 %).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:23][CH2:24][CH3:25])(=[O:22])/[CH:18]=[CH:19]\[CH2:20][CH3:21]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([N:8]1[CH2:9][C@H:19]([CH2:20][CH3:21])[C@H:18]([C:17]([O:23][CH2:24][CH3:25])=[O:22])[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC/C=C\C(=O)OCC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1CC
Reaction time: 48 h
Yield: 96.1 %

Procedure:
To a solution of N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (9.98 mL, 39.0 mmol), and (Z)-ethyl pent-2-enoate (5 g, 39.0 mmol, Preparation #RRR.1) in DCM (50 mL) was added TFA (0.030 mL, 0.390 mmol) at rt. After about 2 d, the reaction mixture was concd in vacuo to provide crude cis-ethyl 1-benzyl-4-ethylpyrrolidine-3-carboxylate (9.8 g, 96%) as an oil. LC/MS (Table 1, Method a) Rt=0.51 min; MS m/z: 262 (M+H)+.
Reaction SMILES: N.[Na].[F:3][C:4]([F:20])([F:19])[C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[CH:6]=1.Br[CH2:22][CH2:23][CH2:24][Cl:25]>CCCCCCC>[Cl:25][CH2:24][CH2:23][CH2:22][N:8]1[C:7]2[CH:6]=[C:5]([C:4]([F:3])([F:19])[F:20])[CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: FC(F)(F)c1ccc2c(c1)Nc1ccccc1S2
Reactant: ClCCCBr
Agent: N
Agent: [Na]
Solvent: CCCCCCC
Product: FC(F)(F)c1ccc2c(c1)N(CCCCl)c1ccccc1S2
Temperature: -40 °C
Yield: 157.1 %

Procedure:
Into a 5 liter reactor fitted with stirring and cooling means and maintained at about -40° C., there were poured 1 liter of liquid ammonia, 11.5 g (0.5 mole) of metallic sodium, 0.5 g of ferric acetate and then, slowly, 133.5 g (0.5 mole) of 2-trifluoromethyl-phenothiazine. The mixture was stirred for one hour and there were added 78.8 g (0.5 mole) of 1-bromo-3-chloropropane. After stirring for some minutes, the mixture was allowed to warm slowly up to room temperature, with elimination of the liquid ammonia. There were then added 2 liters of heptane and stirring was maintained for 12 hours. The mixture was then refluxed for one hour and filtered, washed with heptane, evaporated to dryness and recrystallized from heptane to give 270 g (yield 81%) of N-(γ-chloropropyl)-2-trifluoromethyl-phenothiazine.
Reaction SMILES: [N:1]1([CH:6]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:19][CH:20]([CH3:24])[C:21](O)=[O:22]>>[N:1]1([CH:6]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:21](=[O:22])[CH:20]([Br:19])[CH3:24])[CH3:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(Br)C(=O)O
Reactant: CC(c1cccc(OCCCN)c1)N1CCCC1
Product: CC(Br)C(=O)NCCCOc1cccc(C(C)N2CCCC2)c1

Procedure:
3-[3-[1-(1-Pyrrolidinyl)ethyl]phenoxy]propylamine and bromopropionic acid were reacted in the same way as in Example 6 to afford N-[3-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]propyl]bromopropionamide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1.N.O1CCOCC1.CC[N:21](C(C)C)C(C)C>CCOCC>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:21])=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)c1cc(Cl)nc(Cl)n1
Agent: N
Solvent: CCOCC
Solvent: C1COCCO1
Product: NC(=O)c1cc(Cl)nc(Cl)n1
Reaction time: 8 h
Yield: 41.1 %

Procedure:
To a solution of 2,6-dichloropyrimidine-4-carbonyl chloride (26.13 g, 123.6 mmol) in Et2O (500 mL) was added a mixture of 0.5M ammonia in dioxane (250 mL, 125 mmol) and iPr2NEt (22 mL, 126 mmol) dropwise over approximately 50 minutes. After stirring overnight the reaction was concentrated in vacuo to a residue and chromatographed over silica gel with 10-50% EtOAc in hexanes. The product fractions were evaporated in vacuo, and the resulting solid residue triturated with 10 mL 10% EtOAc/hexanes and filtered to give 2,6-dichloropyrimidine-4-carboxamide as an orange crystalline solid (9.743 g, 50.74 mmol, 41% yield). LC/MS: m/z=192.2 [M+H]+, 1H NMR (400 MHz, DMSO-d6): 8.40 (1H, br s), 8.16 (1H, br s), 8.10 (1H, s).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=1.Br[CH2:15][C:16]([C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1)=O>>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]2[S:8][CH:15]=[C:16]([C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=3)[N:9]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)c1ccc(-c2csc(-c3ccc(C(F)(F)F)cc3)n2)cc1
Yield: 56 %

Procedure:
In the same manner as in Example 74, 4-trifluoromethylthiobenzamide was reacted with ethyl 4-bromoacetylbenzoate to obtain ethyl 4-[2-(4-trifluoromethylphenyl)-4-thiazolyl)benzoate. The product was recrystallized from ethanol. Yield: 56%. Pale yellow prisms. Melting point: 163 to 164° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9]O)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:19])CC)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][F:19])=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(CO)c1ccc(Br)cc1
Solvent: ClCCl
Product: CC(C)(CF)c1ccc(Br)cc1
Reaction time: 4 h

Procedure:
2-(4-Bromophenyl)-2-methylpropan-1-ol (500 mg, 2.182 mmol) was dissolved in Dichloromethane (7.2 mL) in a 20 mL vial. Diethylaminosulfur trifluoride (0.433 mL, 3.27 mmol) was then slowly added To a solution and the resultant mixture was stirred at ambient temperature overnight. At which time, an additional 0.5 eq of DAST was added and stirred for an additional 4 hours. The reaction mixture was purified directly by MPLC on silica gel (eluting with 5% ethyl acetate in hexanes) to afford the title compound. 1H NMR (500 MHz, CDCl3) δ 7.43-7.42 (d, 2H), 7.10-7.09 (d, 2H), 2.88 (s, 1H), 2.83 (s, 1H), 1.35 (s, 3H), 1.30 (s, 3H).
Reaction SMILES: C[C@H]1CC[C@H](N[CH:9]2[CH2:14][CH2:13][N:12](C(=O)C)[CH2:11][CH2:10]2)CC1.C(OC(=O)CSC1SC(N)=NC=1)C.[C:31]([N:34]1[CH2:39][CH2:38][CH:37]([N:40]([C@H:54]2[CH2:59][CH2:58][C@H:57]([CH3:60])[CH2:56][CH2:55]2)[C:41](=[O:53])[NH:42][C:43]2[S:44][C:45]([S:48][CH2:49][C:50]([OH:52])=[O:51])=[CH:46][N:47]=2)[CH2:36][CH2:35]1)(=[O:33])[CH3:32].C1C=C2C(N(O)N=NC2=CC=1)=O.CCN=C=NCCCN(C)C.N1CCCCC1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:31]([N:34]1[CH2:35][CH2:36][CH:37]([N:40]([C@H:54]2[CH2:59][CH2:58][C@H:57]([CH3:60])[CH2:56][CH2:55]2)[C:41](=[O:53])[NH:42][C:43]2[S:44][C:45]([S:48][CH2:49][C:50]([OH:52])=[O:51])=[CH:46][N:47]=2)[CH2:38][CH2:39]1)(=[O:33])[CH3:32].[C:31]([N:34]1[CH2:39][CH2:38][CH:37]([N:40]([C@H:54]2[CH2:59][CH2:58][C@H:57]([CH3:60])[CH2:56][CH2:55]2)[C:41]([NH:42][C:43]2[S:44][C:45]([S:48][CH2:49][C:50](=[O:52])[N:12]3[CH2:13][CH2:14][CH2:9][CH2:10][CH2:11]3)=[CH:46][N:47]=2)=[O:53])[CH2:36][CH2:35]1)(=[O:33])[CH3:32]
Reactant: CC(=O)N1CCC(N[C@H]2CC[C@H](C)CC2)CC1
Agent: CC(=O)N1CCC(N(C(=O)Nc2ncc(SCC(=O)O)s2)[C@H]2CC[C@H](C)CC2)CC1
Agent: CC(=O)N1CCC(N(C(=O)Nc2ncc(SCC(=O)O)s2)[C@H]2CC[C@H](C)CC2)CC1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(=O)N1CCC(N(C(=O)Nc2ncc(SCC(=O)N3CCCCC3)s2)[C@H]2CC[C@H](C)CC2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
{2-[3-(1-Acetyl-piperidin-4-yl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid was prepared from 1-[4-(trans-4-methyl-cyclohexylamino)-piperidin-1-yl]-ethanone and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester as described in general procedure (I). Amide coupling was then performed as follows using general procedure (J): {2-[3-(1-Acetyl-piperidin-4-yl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid is dissolved/suspended in 1 ml of DMF in a 4 ml glass vial equipped with a magnetic stirring bar and a screw cap. 0.015 g (0.088 mmol) of DHOBt+0.017 g (0.088 mmol) of EDAC is added, stirred for 1 h at room temperature (clear yellow mixture) after which 0.088 mmol of piperidine and 0.015 ml (0.088 mmol) of diisopropylethylamine is added. Stirred for 3 days at room temperature and purification by HPLC gave the title compound.
Reaction SMILES: C([N:8]1[CH2:28][CH2:27][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:16][C:17]3[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[C:10]=2[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[F:25][C:23]([F:24])([F:26])[C:20]1[N:19]=[CH:18][C:17]([NH:16][C:15]2[C:10]3[CH2:9][NH:8][CH2:28][CH2:27][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:22][CH:21]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CN(Cc2ccccc2)CC3)cn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CNCC3)cn1
Reaction time: 24 h

Procedure:
6-Benzyl-N-(6-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (1.7 g, 4.4 mmol) was dissolved in methanol (25 mL) and palladium hydroxide was added (0.2 g, 20% wt). The mixture was shaken on a Parr Shaker under H2(g) atmosphere (60 PSI) for 1 day. The mixture was filtered through celite and evaporated to give 1.3 g (quant.) as an orange oil, which was used as such for the next step.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)=[C:15]([CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[CH:16]=1
Reactant: Cc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c(C2CC(C)(C)CC(C)(C)C2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C2=CCNCC2)c(C2CC(C)(C)CC(C)(C)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 124.8 %

Procedure:
To a solution of 4-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (297 mg, 0.72 mmol) produced in Example (104e) in dichloromethane (3 mL) was added trifluoroacetic acid (3 mL), followed by stirring for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, and then saturated aqueous solution of sodium hydrogencarbonate was added to the residue and extraction was performed with ethyl acetate. The organic layer was dried with a desiccant and then filtered. The filtrate was concentrated under reduced pressure to give 280 mg of a crude product of the title compound as a light yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:15][CH2:16][OH:17]>C(O)C>[OH:17][CH2:16][CH2:15][N:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1
Reactant: OCCBr
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: OCCN1CCC(O)CC1

Procedure:
Piperidin-4-ol (5 g, 49.4 mmol) is dissolved in 200 ml of ethanol and anhydrous sodium carbonate (21 g, 197.6 mmol) is added. 2-Bromo-ethanol (6.9 ml, 98.8 mmol) is added dropwise and the reaction mixture is refluxed for 16 hours. After evaporation under reduced pressure the mixture is stirred with 200 ml of DCM and filtered. The clear filtrate is evaporated under reduced pressure and dried at high vacuum.
Reaction SMILES: Br[C:2]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)[CH:17]=1)=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[CH3:33]B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Ag]=O>[F:30][C:29]([F:32])([F:31])[C:26]1[CH:27]=[CH:28][C:23]([O:22][C:18]2[CH:17]=[C:16]([C:2](=[C:3]3[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]3)[CH3:33])[CH:21]=[CH:20][CH:19]=2)=[N:24][CH:25]=1
Reactant: CB(O)O
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)c2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Agent: Cl[Pd]Cl
Agent: O=[Ag]
Agent: [Fe+2]
Solvent: Cc1ccccc1
Product: CC(=C1CCN(C(=O)OC(C)(C)C)CC1)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 85 °C
Yield: 79.3 %

Procedure:
To a solution of tert-butyl 4-(bromo(3-(5-(trifluoromethyl)pyridin-2-yloxy)phenyl)methylene)piperidine-1-carboxylate (Example 71, step 2) (420 mg, 0.818 mmol) in toluene (10 mL), under N2 was added methyl boronic acid (54 mg, 0.900 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (60 mg, 0.0818 mmol), potassium carbonate (226 mg, 1.64 mmol) and silver oxide (379 mg, 1.64 mmol). The reaction was heated to 85° C. overnight. The reaction was cooled down and filtered. The filtrate was washed with water and dried over MgSO4. Purification by silica gel column chromatography (0-5% MeOH/CH2Cl2) gave the title compound (291 mg, 79% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[N:19][C:20]([OH:24])=[C:21]([OH:23])[CH:22]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:16][C:17]1[CH:22]=[C:21]([O:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)[C:20]([OH:24])=[N:19][CH:18]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1cc(Cl)cnc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc(Cl)cnc3O)c2cc1OC
Temperature: 160 °C
Reaction time: 3 h
Yield: 24.7 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (226 mg), 3-chloro-5,6-dihydroxypyridine (290 mg), and 4-dimethylaminopyridine (360 mg) were suspended in o-dichlorobenzene (13 ml), and the suspension was stirred at 160° C. for 3 hr. The reaction solution was cooled to room temperature, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give 4-(5-chloro-2-hydroxy-pyridin-3-yloxy)-6,7-dimethoxyquinoline (83 mg, yield 25%).
Reaction SMILES: COS([O-])(=O)=O.N1([NH+]=[C:13]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)N)CCCC1.[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:21].[OH-].[Na+]>C1(C)C=CC=CC=1>[N:15]1([CH:13]=[C:22]([C:20]#[N:21])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCOC(=O)CC#N
Reactant: NC(=[NH+]N1CCCC1)N1CCCC1
Agent: COS(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=CN1CCCC1
Yield: 95.5 %

Procedure:
Analogously to Example 1, 27.6 g of 95.5% pure dipyrroli-dino-formamidinium methylsulphate were reacted with 11.4 g of ethyl cyanoacetate and 4.0 g of NaOH powder in 140 ml of toluene. After work-up, 95.5% of ethyl pyrrolidino-methylenecyanoacetate were obtained.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[S:7][C:8]=1[C:9](OCC)=[O:10])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH3:3][CH:2]([C:4]1[N:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=2)[S:7][C:8]=1[CH2:9][OH:10])[CH3:1]
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
Ethyl 4-(1-methylethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate (XI-5a) (2.68 g, 7.80 mmol) was dissolved in THF (8 mL) and cooled to 0° C. under nitrogen. Lithium aluminum hydride (1.0M solution in THF, 8.00 mL, 8.00 mmol) was added and the mixture was stirred at 0° C. for 60 min. Water (0.3 mL) was added, followed by 15% aqueous sodium hydroxide (0.3 mL), then water (0.9 mL). The resulting mixture was filtered and the filtrate was concentrated to provide the title compound (2.13 g, 91%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=8.3 Hz, 2H), 7.65 (d, J=8.3 Hz, 2H), 4.86 (d, J=5.2 Hz, 2H), 3.14 (qu, J=6.8 Hz, 1H), 1.33 (d, J=6.8 Hz, 6H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[C:15](Br)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:54][C:55]([F:66])([F:65])[C:56]1[CH:61]=[CH:60][C:59](B(O)O)=[CH:58][CH:57]=1>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[C:15]([C:59]4[CH:60]=[CH:61][C:56]([C:55]([F:66])([F:65])[F:54])=[CH:57][CH:58]=4)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C1C(Br)=C(c2ccc(F)cc2)c2ccc(OCCN3CCOCC3)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: O=C1C(c2ccc(C(F)(F)F)cc2)=C(c2ccc(F)cc2)c2ccc(OCCN3CCOCC3)cc21
Yield: 57 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 6-(2-morpholinoethoxy)-2-bromo-3-(4-fluorophenyl)-1H-inden-1-one obtained in Step 6 of Example 24 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 4-(trifluoromethyl)phenylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (acetone/hexanes=1:4) to obtain the title compound (57%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4](Cl)=[O:5].[H-].[Na+].[Br:15][C:16]1[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][N:17]=1>CN(C=O)C.C(OCC)(=O)C>[Br:15][C:16]1[CH:21]=[C:20]([NH:22][C:4](=[O:5])[C:3]2[C:2]([Cl:1])=[CH:10][C:9]([I:11])=[CH:8][C:7]=2[Cl:12])[CH:19]=[CH:18][N:17]=1
Reactant: O=C(Cl)c1c(Cl)cc(I)cc1Cl
Reactant: Nc1ccnc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1ccnc(Br)c1)c1c(Cl)cc(I)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.4 %

Procedure:
To a cooled (0° C.) solution of 2,6-dichloro-4-iodobenzoyl chloride (70 mg, 0.21 mmol) in DMF (2 mL) was added NaH (17 mg, 0.42 mmol). The mixture was stirred for 10 minutes and then 2-bromopyridin-4-amine (40 mg, 0.23 mmol) was added. The resulting mixture was slowly warmed to 25° C., diluted with ethyl acetate (10 mL), quenched with water (1 mL), washed with saturated Na2CO3 and water, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica-gel chromatography (Pet Ether/EtOAc=20:1 to 3:1) to afford N-(2-bromopyridin-4-yl)-2,6-dichloro-4-iodobenzamide (40 mg, 40% yield). LCMS (ESI) m/z: 470.9 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH2:27])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH:27][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: COc1ccc(C(=O)Nc2nc(C)c(C(=O)NCc3ccccc3)s2)cc1
Yield: 10 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 4-methoxybenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 10% yield; m.p. 203-204° C.; 1H NMR (CDCl3, 300 MHz) δ 7.86 (d, J=8.8 Hz, 2H), 7.35-7.30 (m, 5H), 6.96 (d, J=8.8 Hz, 2H), 5.97 (t, J=5.6 Hz, 1H), 4.58 (d, J=5.6 Hz, 2H), 3.86 (s, 3H), 2.49 (s, 3H); MS (ES+) m/z 382.1 (M+1).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:33](Cl)=[O:34])[CH:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:36]1([CH2:42][CH2:43][OH:44])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:33]([N:39]3[CH2:40][CH2:41][N:36]([CH2:42][CH2:43][OH:44])[CH2:37][CH2:38]3)=[O:34])[C@H:16]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)[C@H:17]([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: OCCN1CCNCC1
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCO)CC1

Procedure:
cis-4-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 20) was reacted with 2-piperazine-1-yl-ethanol (Aldrich) to give cis-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C32H39N6O3Cl2 [(M+H)+] 625.2455, observed 625.2457.
Reaction SMILES: CS[CH:3]1[CH:8]([C:9]#[N:10])[C:7](=[O:11])[NH:6][C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)=[N:4]1.[O:18]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[O:22][CH2:21][CH2:20][CH2:19]1>>[CH2:24]1[C:23]2([O:18][CH2:19][CH2:20][CH2:21][O:22]2)[CH2:28][CH2:27][N:26]([C:3]2[N:4]=[C:5]([CH2:12][C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[NH:6][C:7](=[O:11])[C:8]=2[C:9]#[N:10])[CH2:25]1
Reactant: C1COC2(CCNCC2)OC1
Reactant: CSC1N=C(Cc2ccsc2)NC(=O)C1C#N
Product: N#Cc1c(N2CCC3(CC2)OCCCO3)nc(Cc2ccsc2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-4,6-dihydropyrimidine-5-carbonitrile are reacted with 597 mg (3.80 mmol) of 1,5-dioxa-9-azaspiro[5.5]undecane to give 86 mg (61% of theory) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[C:8]([C:10]1[CH:14]=[CH:13][NH:12][CH:11]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[CH2:25]([N:12]1[CH:13]=[CH:14][C:10]([C:8](=[O:9])[C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:17]([OH:18])=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)=[CH:11]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)c1cc(C(=O)c2cc[nH]c2)cc(C(C)(C)C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C(=O)c2ccn(Cc3ccccc3)c2)cc(C(C)(C)C)c1O
Reaction time: 0.5 h

Procedure:
2 G (6.6 mmol) of 3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole were added to a cooled, stirred suspension of 0.70 g of sodium hydride (50% in mineral oil) in 50 ml of anhydrous dimethylformamide under nitrogen. After 30 minutes at room temperature, 1.0 ml of benzyl bromide was added. Stirring at room temperature was continued for an additional 16 hours. The reaction mixture was poured over a 10% HCl-ice mixture, then extracted three times with 250 ml ethyl acetate. The organic layer was washed five times with 200 ml water, dried and evaporated to dryness. The residue was purified by chromatography on alumina (3% water, 100 g) eluting with hexane:ethyl acetate (9:1). Crystallization from methylene chloride-hexane gave 1.5 g of N-benzyl-3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole (mp 123°-124° C.).