Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]2[CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:11][O:12][C:8]=2[CH:7]=1.[H-].[Na+].C=[O:27]>CN(C=O)C>[Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]2[C:10]([OH:27])([C:13]([O:15][CH3:16])=[O:14])[CH2:11][O:12][C:8]=2[CH:7]=1
Reactant: C=O
Reactant: COC(=O)C1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(O)COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Reaction time: 0.5 h
Yield: 9.9 %

Procedure:
To a mixture of methyl 6-((2,4-dichlorobenzyl)oxy)-2,3-dihydro-1-benzofuran-3-carboxylate (120 mg) in DMF (dry) (3.4 mL) was added sodium hydride (15.0 mg) at 0° C. After stirring for 30 min, to the mixture was added paraformaldehyde (20.4 mg) at 0° C. The mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The mixture was quenched with saturated aqueous NH4Cl at 0° C. and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (12.4 mg).
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=1)[CH:12]=O>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.CCCCCC.C1COCC1>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:12]=[CH:1][CH3:2])[CH:14]=1
Reactant: [Li]CCCC
Reactant: O=Cc1cc(Br)ccc1F
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC=Cc1cc(Br)ccc1F
Temperature: -50 °C
Reaction time: 1 h

Procedure:
A mixture of 16.5 g (0.044 mol) of ethyltriphenylphosphonium bromide and 387 ml of anhydrous THF is cooled to -50° C. under a nitrogen atmosphere. 27.8 ml (0.044 mol) of a 1.6M solution of n-butyllithium in hexane are added dropwise. The mixture is allowed to return to 0° and is stirred for 1 h at 0° C. The mixture is cooled to -30° C. and a solution of 8.8 g (0.0433 mol) of 5-bromo-2-fluorobenzaldehyde in 43 ml of anhydrous THF is added dropwise. The mixture is stirred overnight at room temperature and then for 2 h at 40° C. Filtration is carried out and the filtrate is evaporated under vacuum.
Reaction SMILES: [C:1]([C:3]([C:14](=[O:30])[N:15]([CH2:26][CH2:27]CC)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)=[CH:4][NH:5][C:6](=[NH:13])[N:7]1[CH2:11][CH2:10][NH:9][C:8]1=[O:12])#[N:2].[C:31](O)(=O)C(O)=O>C(O)(=O)C>[CH2:26]([N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=1)[C:14]([C:3]1[C:1]([NH2:2])=[N:13][C:6]([N:7]2[CH2:11][CH:10]([CH3:31])[NH:9][C:8]2=[O:12])=[N:5][CH:4]=1)=[O:30])[CH3:27]
Reactant: O=C(O)C(=O)O
Reactant: CCCCN(C(=O)C(C#N)=CNC(=N)N1CCNC1=O)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: CCN(C(=O)c1cnc(N2CC(C)NC2=O)nc1N)c1cccc(C(F)(F)F)c1
Reaction time: 3 h
Yield: 173.2 %

Procedure:
A mixture of 4.084 g (10 mmol) of a compound II (R1 =CH3 ; R2, R3, R5, R6 =H; R4 =C2H5), 360 mg (4 mmol) of anhydrous oxalic acid and 9 ml of glacial acetic acid was stirred at 60° for 3 hours and then worked up as described in Example 5. 2.83 g (69.3% yield) of pure 4-amino-2-(4-methyl-2-oxo-1-imidazolidinyl)pyrimidine-5-carboxylic acid N-ethyl-N-(3-trifluoromethylphenyl)amide were obtained (by crystallization from ether) after drying, melting point 208°-209°.
Reaction SMILES: B(Br)(Br)Br.C1[O:27][C:26]2[CH:25]=[CH:24][C:9]([CH:10]=[C:11]3[CH2:20][CH2:19][C:18]4[C:13]([CH3:22])([CH2:14][CH2:15][C:16](=[O:21])[CH:17]=4)[C:12]3=[O:23])=[CH:8][C:7]=2[O:6]1.C(=O)([O-])[O-].[K+].[K+].CO>ClCCl.O>[OH:6][C:7]1[CH:8]=[C:9]([CH:24]=[CH:25][C:26]=1[OH:27])[CH:10]=[C:11]1[CH2:20][CH2:19][C:18]2[C:13]([CH3:22])([CH2:14][CH2:15][C:16](=[O:21])[CH:17]=2)[C:12]1=[O:23]
Reactant: CC12CCC(=O)C=C1CCC(=Cc1ccc3c(c1)OCO3)C2=O
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC12CCC(=O)C=C1CCC(=Cc1ccc(O)c(O)c1)C2=O

Procedure:
A solution of boron tribromide (0.28 ml, 0.003 mole) in dichloromethane (15.1) was added to a well stirred solution of 2-(3,4-methylenedioxybenzylidene)-3,4,8,8a-tetrahydro-8a-methyl-1,6(2H,7H)-naphthalenedione (9) (0.3 g, 0.001 mole) in dichloromethane (20 ml) containing potassium carbonate (1.0 g) at -78° C. under nitrogen. After 10 minutes the mixture was treated with methanol (1 ml) and poured into water. The organic phase was separated and dried (Na2SO4). The solvent was removed and the product was chromatographed on silica gel using ether as eluant. The title compound was obtained as a yellow crystalline solid (0.05 g, 17%) m.p. 193°-5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:29]=[CH:28][C:17]4[O:18][CH2:19][C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[CH:22](O)[C:16]=4[CH:15]=3)=[N:9]2)=[CH:4][C:3]=1[S:30][CH2:31][CH3:32].[SH:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37]>>[C:36]([CH2:35][CH2:34][S:33][CH:22]1[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[CH2:19][O:18][C:17]2[CH:28]=[CH:29][C:14]([O:13][CH2:12][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([S:30][CH2:31][CH3:32])[CH:4]=4)[N:9]=3)=[CH:15][C:16]1=2)([OH:38])=[O:37]
Reactant: O=C(O)CCS
Reactant: CCSc1cc2ccc(COc3ccc4c(c3)C(O)c3ccccc3CO4)nc2cc1Cl
Product: CCSc1cc2ccc(COc3ccc4c(c3)C(SCCC(=O)O)c3ccccc3CO4)nc2cc1Cl

Procedure:
2-(7-Chloro-6-ethylthioquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: C([NH:8][C@H:9]([C:14]1[NH:18][C:17]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:16]=2[N:15]=1)[CH2:10][CH2:11][O:12][CH3:13])(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>ClCCl>[Cl:23][C:21]1[CH:20]=[CH:19][C:17]2[NH:18][C:14]([C@@H:9]([NH2:8])[CH2:10][CH2:11][O:12][CH3:13])=[N:15][C:16]=2[CH:22]=1
Reactant: COCC[C@H](NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCC[C@H](N)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1g from (1S)—N-Boc-1-(5-chloro-1H-benzimidazol-2-yl)-3-methoxy-propylamine and TFA in dichloromethane.
Reaction SMILES: C([Li])CCC.CCCCCC.CCN(C(C)C)C(C)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:36]=[C:35]3[C:30]([CH:31]=[CH:32][CH:33]=[CH:34]3)=[N:29]2)=[CH:24][CH:23]=1.[CH:37]1([CH:43]=[O:44])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>C1COCC1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:36]([CH:43]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[OH:44])=[C:35]3[C:30]([CH:31]=[CH:32][CH:33]=[CH:34]3)=[N:29]2)=[CH:24][CH:23]=1
Reactant: Clc1ccc(-n2cc3ccccc3n2)cc1
Reactant: O=CC1CCCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: OC(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 43 %

Procedure:
A 1.6 M solution of n-butyllithium in hexane (5.7 ml, 9.1 mmol) was added within 10 min to a −78° C. cold solution of N,N′-diisopropylethylamine (1.55 ml, 9.1 mmol) in THF (25.5 ml). The solution was stirred for 10 min at 5° C. and cooled again to −78° C. A solution of 2-(4-chloro-phenyl)-2H-indazole (1.7 g, 7.4 mmol; Liu, Rui; Zhu, Yong-ming; Qin, Lie-na; Ji, Shun-jun; Katayama, Haji. Heterocycles (2007), 71(8), 1755-1763.) in THF (8.5 ml) was added, the suspension was stirred for 15 min at 0° C., cooled to −78° C. and cyclohexane-carbaldehyde (1.1 ml, 9.1 mmol; CAS Reg. No. 2043-61-0) was added. The reaction mixture was stirred at ambient temperature for 14 h. Under ice cooling saturated aqueous ammonium chloride solution was added and the mixture was extracted two times with iPrOAc. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, iPrOAc/heptane) to give the title compound (1.1 g, 3.2 mmol; 43%) as yellow foam. MS: m/e=341.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4([OH:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH:29]1([CH:32]=O)[CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4([OH:28])[CH2:27][CH2:26][N:25]([CH2:32][CH:29]5[CH2:31][CH2:30]5)[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc2)CCNCC1
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OC1(c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc2)CCN(CC2CC2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 0.78 g (2.02 mmol) of 4-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenyl}piperidin-4-ol and 0.59 mL (8.06 mmol) of cyclopropanecarbaldehyde in 40 mL of THF was stirred for 30 minutes at RT, then combined with 1.71 g (8.06 mmol) of sodium triacetoxyborohydride and 0.46 mL (8.06 mmol) of glacial acetic acid and stirred for a further 2 days at RT. The reaction mixture was combined with DCM, and the organic phase was washed with semisaturated aqueous sodium bicarbonate solution, dried over sodium sulfate, and evaporated down in vacuo. The crude product was stirred with isopropanol, and the precipitate was filtered off and dried in vacuo. Yield: 0.19 g (21% of theoretical); C28H27ClN2O (M=442.980); calc.: molpeak (M+H)+:443/445 (Cl); found: molpeak (M+H)+:443/445 (Cl); HPLC-MS: 7.26 minutes (method A).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:25]([O:27][C:28](=[O:37])[C@@:29]([CH3:36])([C:32]([NH:34][CH3:35])=[O:33])[NH:30][CH3:31])[CH3:26].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:25]([O:27][C:28](=[O:37])[C:29]([N:30]([CH3:31])[C:20]([C:19]1[CH:23]=[CH:24][C:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:17][CH:18]=1)=[O:21])([CH3:36])[C:32]([NH:34][CH3:35])=[O:33])[CH3:26]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)[C@](C)(NC)C(=O)NC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C)(C(=O)NC)N(C)C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.9 %

Procedure:
DIPEA (1.0 mL) and 4-phenylbenzoyl chloride (0.50 g) were added in this order to a chloroform (10 mL) solution of O-ethyl-N,N2,2-trimethyl-3-oxoserinamide (Intermediate 9-1, 0.69 g), and the mixture was stirred for 5 hours at room temperature. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, whereafter the desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel chromatography (gradient elution with hexane/ethyl acetate=60/40→25/75) to obtain 4-{[1-ethoxy-2-methyl-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}biphenyl (colorless oil) (0.79 g, 66%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][NH2:14].O1CCOC[CH2:16]1>C(O)=O>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]2[CH:16]=[N:13][N:14]=[C:2]2[CH:11]=1
Reactant: NN
Reactant: Clc1cc(Cl)c2ccccc2n1
Reactant: C1COCCO1
Solvent: O=CO
Product: Clc1cc2nncn2c2ccccc12

Procedure:
2,4-Dichloroquinoline (1.0 mole) was combined with 1 mole of anhydrous hydrazine in 4 liters of dioxane. The reaction mixture was heated at reflux for 12 hours at which time the reaction mixture was allowed to cool and the dioxane was stripped off. The resultant solid was refluxed for twelve hours in formic acid, then allowed to cool and the formic acid stripped off. The 5-chloro-s-triazolo(4,3-a)quinoline was then isolated and purified by column chromatography. A silica gel column was used with a 5 percent methanol/95 percent ethyl acetate solution as the eluant. The purified product melted at 242°-3.5°C.
Reaction SMILES: N(OC(C)(C)C)=O.I[CH2:9][I:10].NC1[S:13][CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=1>C(#N)C.[Cl-].[Na+].O>[CH2:20]([O:19][C:17]([C:15]1[N:16]=[C:9]([I:10])[S:13][CH:14]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)c1csc(N)n1
Reactant: ICI
Agent: CC(C)(C)ON=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1csc(I)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
A solution of 6.0 ml of t-butyl nitrite in 120 ml of acetonitrile was cooled in ice under an argon atmosphere, and 9.64 g of diiodomethane and 5.16 g of 2-amino-4-ethoxycarbonylthiazole were added to the cooled solution. The mixture was stirred at room temperature for one hr, brine was added thereto, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, were washed twice with brine, were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1 to 3:1) to give 5.58 g of 4-ethoxycarbonyl-2-iodothiazole.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([OH:19])([C:14]#[C:15][CH:16]1[CH2:18][CH2:17]1)[C:10]([F:13])([F:12])[F:11].[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21]>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:20](=[O:21])[O:19][C:9]([C:14]#[C:15][CH:16]3[CH2:18][CH2:17]3)([C:10]([F:13])([F:11])[F:12])[C:3]=2[CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(Cl)cc1C(O)(C#CC1CC1)C(F)(F)F
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C(C#CC2CC2)(C(F)(F)F)O1
Yield: 100.4 %

Procedure:
A solution of 2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol (15.00 g, 0.0518 mol) and 41.98 g (0.259 mol) of 1,1'-carbonyldiimidazole in 250 mL of dry THF was stirred under argon at 55° C. for 24 hours. The solvent was removed on a rotary evaporator and the residue was partitioned between 500 mL of ethyl acetate and 400 mL of water. The layers were separated and the aqueous phase was extracted once more with ethyl acetate. The combined ethyl acetate extracts were washed with 2×200 mL of 2% aqueous HCl, saturated aqueous NaHCO3, and brine. Drying over MgSO4, filtration, and removal of the solvent in vacuo provided 16.42 g of the title compound as a solid. Recrystallization from ethyl acetatehexane afforded 12.97 g of analytically pure (+) 6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H -3,1-benzoxazin-2-one as a white crystals. mp: 178°-180° C. 1H-NMR (CDCl3): 0.85 (m, 2H), 0.94 (m, 2H), 1.40 (m, 1H), 6.81 (d, J=8.5 Hz, 1H), 7.37 (dd, J=2.5, 8.5 Hz, 1H), 7.49 (d, J=2.5 Hz, 1H), 8.87 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[S:9][C:8]([CH:10]=[O:11])=[CH:7][CH:6]=1.[BH4-].[Na+].O>C(O)C>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[S:9][C:8]([CH2:10][OH:11])=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(Cc2ccccc2F)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCc1ccc(Cc2ccccc2F)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
5-(2-Fluoro-benzyl)-thiophene-2-carbaldehyde described in Preparation Example 123 (2.81 g, 12.7 mmol) was dissolved in ethanol (40 mL), sodium borohydride (964 mg, 25.4 mmol) was added at 0° C., and the solution was stirred at room temperature for 1 hour. Water was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1), and the title compound (2.10 g, 9.45 mmol, 74%) was obtained as a colorless oil.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[F:6][C:7]([F:18])([C:14]([F:17])([F:16])[F:15])[CH2:8][CH2:9][CH2:10][CH2:11]C#N.[OH2:19]>>[F:6][C:7]([F:18])([C:14]([F:17])([F:16])[F:15])[CH2:8][CH2:9][CH2:10][C:11]([OH:2])=[O:19]
Reactant: N#CCCCCC(F)(F)C(F)(F)F
Reactant: O=S(=O)(O)O
Reactant: O
Product: O=C(O)CCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
Concentrated sulfuric acid (350 ml) was slowly added dropwise to 5,5,6,6,6-pentafluorohexanecarbonitrile (108 g, 577.20 mmol) at 0° C., and the resulting mixture was stirred for 3 hours at room temperature. Water (350 ml) was slowly added dropwise to this mixture at 0° C., followed by heating under reflux for 12 hours. After cooling to room temperature, water was added to the reaction mixture, which was then extracted three times with dichloromethane. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off to give 5,5,6,6,6-pentafluorohexanoic acid (95.8 g, Yield 85%).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][C:13]1[N:18]=[C:17]2[S:19][C:20]3[CH2:21][N:22]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][CH2:24][C:25]=3[C:16]2=[C:15]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=2)[C:14]=1[Cl:43].C(N(CC)CC)C>ClCCl>[CH2:26]([N:22]1[CH2:23][CH2:24][C:25]2[C:16]3[C:17]([S:19][C:20]=2[CH2:21]1)=[N:18][C:13]([CH2:12][NH:11][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])=[C:14]([Cl:43])[C:15]=3[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COc1ccc(-c2c(Cl)c(CN)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2c(Cl)c(CNS(=O)(=O)c3ccccc3)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Reaction time: 1 h
Yield: 55.3 %

Procedure:
Benzenesulfonyl chloride (0.156 g) was added to a mixture of the compound (0.35 g) obtained in Example 18B, triethylamine (0.096 g) and dichloromethane (8 ml) under ice-cooling, the mixture was stirred for 1 hour, the reaction mixture was washed successively with water, an aqueous saturated solution of sodium bicarbonate and water, dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to yield 7-benzyl-3-chloro-4-(3,4-dimethoxyphenyl)-2-phenylsulfonylaminomethyl-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']dipyridine (0.25 g, 55%), which was then recrystallized from ethyl acetate-hexane to yield colorless prismatic crystals having a melting point of 153 to 154° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH:5](O)[CH2:6][NH:7][C:8]1[NH:9][CH2:10][CH2:11][N:12]=1.S(=O)(=O)(O)O>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[N:12]3[CH2:11][CH2:10][NH:9][C:8]3=[N:7][CH2:6]2)[CH:14]=[CH:15][CH:16]=1
Reactant: OC(CNC1=NCCN1)c1cccc(Cl)c1
Agent: O=S(=O)(O)O
Product: Cl
Product: Clc1cccc(C2CN=C3NCCN32)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4 parts of m-chloro-α-(2-imidazolin-2-ylaminomethyl)-benzyl alcohol are added portionwise to 20 parts of cooled (ice-bath) sulfuric acid solution 80%. Upon completion, the whole is stirred for 2 hours at room temperature. The reaction mixture is poured onto crushed ice and the whole is filtered over diatomaceous silica. The filtrate is alkalized with ammonium hydroxide solution at room temperature (cooling is necessary) and the product in base form is extracted with chloroform. The latter is dried and evaporated. The residue is converted into the hydrochloride salt in 2-propanol, yielding 5-(m-chlorophenyl)-2,3,5,6-tetrahydro-1H-imidazo[1,2-a]imidazole hydrochloride; m.p. 249.8°C.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH:26]C(=O)OC(C)(C)C)[CH2:24][CH3:25])=[CH:19][CH:18]=1.B(Br)(Br)Br.C(Cl)[Cl:39]>>[ClH:39].[NH2:26][C@@H:23]([C:20]1[CH:19]=[CH:18][C:17]([C:4]2[C:5]3[C:6]4[CH:16]=[CH:15][S:14][C:7]=4[C:8](=[O:13])[NH:9][C:10]=3[CH:11]=[CH:12][C:3]=2[OH:2])=[CH:22][CH:21]=1)[CH2:24][CH3:25]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(-c2c(OC)ccc3[nH]c(=O)c4sccc4c23)cc1
Reactant: ClCCl
Agent: BrB(Br)Br
Product: CC[C@@H](N)c1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Product: Cl
Temperature: 25 °C
Yield: 67 %

Procedure:
Following General Procedure F, (R)-tert-butyl 1-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propylcarbamate (70 mg, 0.15 mmol) in CH2Cl2 at 0° C. was added BBr3 (1.0 M in CH2Cl2, 3 mL, 3 mmol) and the reaction was warmed to room temperature for 4 h. The reaction was quenched by pouring onto water or ice-water and the resulting mixture was concentrated and purified by preparatory HPLC (C18 silica, acetonitrile/water (with 0.05% TFA) gradient). The desired product was dissolved in aqueous HCl, concentrated and dried under high vacuum to afford the desired product as a light yellow solid (35 mg, 67%): 1H NMR (500 MHz, CD3OD) δ 7.61 (s, 2H), 7.55 (d, J=5.4 Hz, 1H), 7.45-7.40 (m, 3H), 7.18 (d, J=8.9 Hz, 1H), 6.03 (d, J=5.4 Hz, 1H), 4.32 (dd, J=9.2, 5.9 Hz, 1H), 2.23-2.01 (m, 2H), 1.04 (t, J=7.4 Hz, 3H); ESI MS m/z 351 [C20H18N2O2S+H]+; HPLC >99% (AUC), tR=8.06 min.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C@H:7]1[N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:15][C@@:6]21[CH3:24].B(Br)(Br)Br>C(Cl)(Cl)Cl>[C:18]1([CH2:17][CH2:16][N:13]2[C@@H:7]3[N:8]([CH3:12])[C:9]4[C:5]([C@:6]3([CH3:24])[CH2:15][CH2:14]2)=[CH:4][C:3]([OH:2])=[CH:11][CH:10]=4)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc2c(c1)[C@]1(C)CCN(CCc3ccccc3)[C@@H]1N2C
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Product: CN1c2ccc(O)cc2[C@]2(C)CCN(CCc3ccccc3)[C@H]12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution under nitrogen of 3.22 g of (3aS-cis)-1,2,3,3a,8,8a-hexahydro-5-methoxy-1-(2-phenylethyl)-3a,8-dimethylpyrrolo[2,3-b]indole in 50 ml of degassed chloroform is added dropwise at 0° C. a solution of 10.1 g of boron tribromide in 50 ml of degassed chloroform. The mixture is stirred for about 3 days at room temperature, cooled to 0° C and cautiously quenched by the dropwise addition of water. The mixture is stirred vigorously for 0.5 hour, and a sufficient volume of saturated aqueous sodium bicarbonate solution is added to make the system just basic to a pH paper. The organic phase is separated, dried over anhydrous sodium sulfate and concentrated. The residue is Kugelrohr distilled at 0.1 mm Hg at an oven temperature of 160°-200° to provide pure (3aS-cis)-1,2,3,3a,8,8a-hexahydro-1-(2-phenylethyl)-3a,8-dimethylpyrrolo[2,3-b]indol-5-ol.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([CH3:9])[C:7]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[N:6][CH:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[Cl:22])[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[C:34]([OH:36])=[O:35]>>[Cl:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[CH:5]1[N:6]=[C:7]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[N:8]([CH3:9])[C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[C:34]([OH:36])=[O:35])=[C:4]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)N(C)C(c2nccs2)=NC1c1ccc(F)cc1Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)N(C)C(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 18.7 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-1-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.48 g, 1.02 mmol) was reacted with morpholine-3-carboxylic acid (0.4 g, 3.06 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.1 g, 20%). The compound was characterized by the following spectroscopic data: