Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.[C:12]1([N:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)N)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:20]1([N:18]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:2]3[CH2:3][C:4]4[C:9]([C:1]2=3)=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: O=C1CCc2ccccc21
Agent: Cl
Product: c1ccc(-n2c3c(c4ccccc42)Cc2ccccc2-3)cc1

Procedure:
The general procedure of Example A is followed. The reaction of 1-indanone and N,N-diphenylhydrazine hydrochloride gives 5-phenyl 5,10-dihydroindeno[1,2-b]indole. It then reacts with n-butyllithium to produce its lithium salt, which in turn reacts with zirconium tetrachloride to produce Catalyst II.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.Cl.[CH3:13][O:14][C:15](=[O:22])[C@H:16]([CH2:18][CH2:19][S:20][CH3:21])[NH2:17].N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:17][C@H:16]([C:15]([O:14][CH3:13])=[O:22])[CH2:18][CH2:19][S:20][CH3:21])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: COC(=O)[C@@H](N)CCSC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CCl)cc1
Reaction time: 12 h
Yield: 63.3 %

Procedure:
A mixture of 4-(chloromethyl)-benzoyl chloride (0.189 g, 1 mmol), methionine methyl ester hydrochloride (0.199 g, 1 mmol), and 0.5 ml of pyridine in 5 ml of chloroform was stirred for 12 hours. The organic solution was washed with 10% HCl, brine, and dried over MgSO4. Flash chromatography of the residue afforded 0.20 g of desired product (64%).
Reaction SMILES: [CH3:1][N:2]([CH2:16][CH2:17][OH:18])[C:3](=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25]>>[CH3:1][N:2]([CH2:16][CH2:17][O:18][C:24]([C:20]1[O:19][CH:23]=[CH:22][CH:21]=1)=[O:25])[C:3](=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCC(=O)N(C)CCO
Reactant: O=C(Cl)c1ccco1
Product: CCCCCCCCCCCC(=O)N(C)CCOC(=O)c1ccco1

Procedure:
N-methyl-N-(2-furoyloxyethyl)lauramide was prepared by the procedure of example 1 from 26 gms. (0.1 mole) of N-methyl-N-(2-hydroxyethyl)lauramide and 13 gms. (0.1 mole) of furoyl chloride. The structure of the final product was characterized on the basis of IR and NMR spectral analyses as described in example 1.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2([F:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]#[C:12]2)=[CH:6][CH:5]=1.[Li+].[OH-]>O1CCOCC1.O>[F:19][C:11]1([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:20])=[O:2])=[CH:9][CH:8]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]#[C:12]1
Reactant: COC(=O)c1ccc(CC2(F)C#CCCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(CC2(F)C#CCCCCC2)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of cyclooctyne 8b (1.8 g, 6.6 mmol) in dioxane (30 mL) and H2O (7.5 mL) was added finely crushed LiOH (3.1 g, 130 mmol). The suspension was heated to 50° C. and stirred for 3 h. The dioxane was removed on a rotary evaporator and the reaction mixture was diluted with CH2Cl2 (100 mL). The organic layer was washed with 1 N HC, (2×100 mL), H2O (3×100 mL), and brine (1×25 mL), and dried over MgSO4, yielding a white solid (1.7 g, 98%, Rf=0.30 in 27:3:1 hexane/EtOAc/AcOH), mp 132.0-132.5° C. (dec). IR: 3442, 2926, 2851, 2674, 2557, 2224, 1686, 1611 cm−1. 1H NMR (DMSO-d6, 400 MHz): δ 1.39 (app quintet, 1H, J=7.6 Hz), 1.64 (m, 2H), 1.76 (m, 2H), 2.10 (m, 5H), 3.07 (s, 1H), 3.11 (d, 1H, J=8.0 Hz), 7.38 (d, 2H, J=8.0 Hz), 7.87 (d, 2H, J=8.4 Hz), 12.9 (br s, 1H). 13C NMR (DMSO-d6, 100 MHz): δ 19.8, 25.7, 29.0, 33.7, 43.7 (d, J=25.0 Hz), 47.6 (d, J=25.0 Hz), 90.7 (d, J=32.0 Hz), 95.4 (d, J=173.0 Hz), 104.5 (d, J=10.0 Hz), 129.0, 129.2, 130.4, 141.2, 167.2. 19F NMR (CD3CN, 376 MHz): δ −139.4 (m). FAB—HRMS: Calcd. for C16H18O2F+ [M+H]+: 261.1291, found: 261.1291. Anal. calcd. for C16H17O2F: C, 79.31; H, 7.49. Found: C, 79.07; H, 7.26.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[NH:10][CH:11]([CH2:14][O:15][CH3:16])[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]I.[H-].[Na+]>C1COCC1.CN(C=O)C>[CH2:1]([O:8][C:9](=[O:17])[N:10]([CH:11]([CH2:14][O:15][CH3:16])[CH2:12][CH3:13])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CCC(COC)NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCC(COC)N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
To a solution of (1-methoxymethyl-propyl)-carbamic acid benzyl ester (4.4 g, 18.5 mmol, 1.0 eq.) and MeI (6.9 mL, 111 mmol, 6 eq.) in THF/DMF (4:1, 50 mL) at 0° C. was slowly added NaH (1.35 g, 55.5 mmol, 3 eq.). The resulting mixture was warmed to room temperature and stirred over night. The reaction was quenched carefully by slow addition of water until no bubbling (H2) was observed. The reaction mixture was poured over ice water and extracted with 3×EtOAc. The combined organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (30% to 50% EtOAc-hexanes) to give (1-methoxymethyl-propyl)-methyl-carbamic acid benzyl ester (4.4 g, 94%).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][O:16][CH3:17])[C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:9][C:5]=1[C:6](O)=[O:7])#[N:2].[NH2:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1>C(O)(=O)C>[CH3:17][O:16][CH2:15][CH2:14][O:13][C:11]1[CH:12]=[C:4]2[C:5](=[CH:9][C:10]=1[O:18][CH2:19][CH2:20][O:21][CH3:22])[C:6]([OH:7])=[N:2][C:1]([NH:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1)=[CH:3]2
Reactant: COCCOc1cc(CC#N)c(C(=O)O)cc1OCCOC
Reactant: Cc1cc(N)n[nH]1
Solvent: CC(=O)O
Product: COCCOc1cc2cc(Nc3cc(C)[nH]n3)nc(O)c2cc1OCCOC
Temperature: 130 °C
Yield: 79.6 %

Procedure:
A mixture of 2-Cyanomethyl-4,5-bis-(2-methoxy-ethoxy)-benzoic acid (2 g, 6.47 mmol), 3-amino-5-methylpyrazol (1.26 g, 12.9 mmol) in acetic acid (10 ml) was sealed in microwave process vial (20 ml). The mixture was heated at 130° C. for 30 minutes under microwave irradiation. After removal of acetic acid, the residue was dissolved in 1 ml MeOH, and this solution was added dropwise to 20 ml water. After stirred for half an hour, solid was collected and dried to give product (2 g, 79.7%). LC-MS: m/e 389(MH+).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13](Cl)=[N:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>C(O)C>[CH2:1]([NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([NH:19][NH2:20])=[N:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccccc1)c1ccc(Cl)nc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1ccc(C(=O)NCc2ccccc2)cn1
Yield: 78 %

Procedure:
Combined N-benzyl-6-chloronicotinamide (13 g, 52.8 mmol) and ethanol (60 mL) then added hydrazine hydrate (85%, 30 mL) drop wise at room temperature. After the addition, the solution was heated to reflux overnight. The reaction mixture was then concentrated to remove ethanol and a solid was obtained. The solid was collected by filtration, washed with EtOAc (3×20 mL), and dried under reduced pressure to give the title compound (10 g, 78%) as an off-yellow solid.
Reaction SMILES: I[C:2]1[C:3]([CH:13]([CH3:15])[CH3:14])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:16][N:17](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:16]([C:2]1[C:3]([CH:13]([CH3:15])[CH3:14])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:17]
Reactant: COC(=O)c1cc(I)c(C(C)C)cc1C
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(C#N)c(C(C)C)cc1C
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 83 %

Procedure:
To a dried round bottom flask was added methyl 5-iodo-4-isopropyl-2-methylbenzoate (compound 198.2, 2.00 g, 6.29 mmol, 1.0 equiv), zinc cyanide (1.48 g, 12.6 mmol, 2.0 equiv), DMF (20 mL) and Pd(PPh3)4 (364 mg, 0.315 mmol, 0.05 equiv). The system was purged with nitrogen followed by argon and the mixture was heated at 100° C. for 15 hours. The reaction was allowed to cool to room temperature then diluted with ethyl acetate (50 mL) and quenched with 1 M FeSO4 (25 mL). The mixture was stirred vigorously for 40 minutes then filtered through celite and washed with 1 M FeSO4 (15 mL), water (50 mL) and ethyl acetate (150 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine (4×100 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The product was purified by silica column chromatography (hexanes to 8% ethyl acetate) to obtain the title compound (1.14 g, 83%). 1H NMR (400 MHz, CDCl3): δ 8.19 (s, 1H), 7.25 (s, 1H), 3.91 (s, 3H), 3.37 (septet, J=6.8 Hz, 1H), 2.67 (s, 3H), 1.32 (d, J=6.8 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:6]1[O:7][C:8]2[C:14]([NH:15][C:16](=O)[O:17]CC)=[C:13]([F:21])[CH:12]=[C:11]([Cl:22])[C:9]=2[N:10]=1)([CH3:5])[CH3:4].C[O-].[Na+].[NH2:26]/[C:27](/[C:34]([F:37])([F:36])[F:35])=[CH:28]\[C:29]([O:31]CC)=O.N12CCCN=C1CCCCC2>CN(C)C=O>[CH3:1][O:2][C:3]([C:6]1[O:7][C:8]2[C:14]([N:15]3[C:29](=[O:31])[CH:28]=[C:27]([C:34]([F:35])([F:36])[F:37])[NH:26][C:16]3=[O:17])=[C:13]([F:21])[CH:12]=[C:11]([Cl:22])[C:9]=2[N:10]=1)([CH3:5])[CH3:4]
Reactant: CCOC(=O)Nc1c(F)cc(Cl)c2nc(C(C)(C)OC)oc12
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(C)(C)c1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c2o1
Yield: 59.3 %

Procedure:
An additional 0.6 gram of 3-[2-(1-methoxy-1-methylethyl)-4-chloro-6-fluorobenzoxazol-7-yl)-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione was prepared in the manner of Step E, Example 1, with 0.8 gram (2.4 mmole) of ethyl N-[2-(1-methoxy-1-methylethyl)-4-chloro-6-fluorobenzoxazol-7-yl]carbamate, 0.15 gram (2.8 mmole) of sodium methoxide, 0.44 gram (2.4 mmole) of ethyl 3-amino-4,4,4-trifluorocrotonate, 30 mL of N,N-dimethylformamide, arid 0.37 gram (2.4 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene as reagents. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].C(O)=O>C(OCC)(=O)C.[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)/C=C/c1ccc(C#N)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O=CO
Product: CCOC(=O)CCc1ccc(C#N)cc1
Temperature: 90 °C
Yield: 97.2 %

Procedure:
Pd/C (0.6 g, 10%, 50% water wet) was added to a solution of ethyl (2E)-3-(4-cyanophenyl)-2-propenoate (2.7 g, 13.42 mmol) in ethyl acetate (40 mL) under an argon atmosphere. It was mixed with TEA (3.74 mL, 26.8 mmol) and formic acid (2.57 mL, 67.1 mmol). The reaction mixture was refluxed at 90° C. under argon for 1 h. It was filtered through a Celite pad. The filtrate was then washed with water, 5% NaHCO3 solution and brine, dried over Na2SO4, and concentrated to provide the title compound as a pale yellow oil (2.65 g, 97% yield). LCMS: rt=2.94 min, [M+H+]=204.0
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[S:11][C:10]2=[N:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:14][N:9]2[N:8]=1.[OH-].[Na+].CN(C)[CH:25]=[O:26]>>[CH3:6][C:7]1[S:11][C:10]2=[N:12][C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:14]([CH:25]=[O:26])[N:9]2[N:8]=1
Reactant: CN(C)C=O
Reactant: Cc1nn2cc(-c3ccccc3)nc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nn2c(C=O)c(-c3ccccc3)nc2s1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
60 ml of phosphorus oxychloride were added dropwise to 180 ml of dimethylformamide, whilst cooling. A further 400 ml of dimethylformamide, and 130 g (0.6 mole) of 2-methyl-6-phenylimidazo[2,1-b]-1,3,4-thiadiazole were then added and the mixture was warmed to 100° C. for 2 hours. It was poured onto 3 kg of ice, 410 g of 40% strength sodium hydroxide solution were added and the mixture was heated rapidly to 90° C. After 5 minutes, it was cooled and the product was filtered off. Yield: 132 g (90% of theory) of melting point 152° to 153° C.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]#[N:25])=[N:6][C:5]([C:3]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2ccn(Cc3ccccc3)c(=O)c12
Temperature: 25 °C
Yield: 67 %

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (25 mg, 0.075 mmol), glycine (745 mg, 9.9 mmol) and NaOMe solution (15 mL, 7.5 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and water (30 mL). 1 M HCl was added with vigorous stirring until pH was about 2. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was dried over MgSO4 and concentrated. The crude product was chromatographed (20-100% EtOAc/hexanes+2% AcOH) to give 19 mg of the title compound as an off-white solid. MS: (+) m/z 378.95 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])=[C:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[C:5](=[CH:6][C:7]([O:31][CH3:32])=[C:8]([O:29][CH3:30])[CH:9]=2)[N:4]=1.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl>[CH3:30][O:29][C:8]1[CH:9]=[C:10]([C:11]2[C:19]3[C:24](=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[N:4]=[C:3]([CH2:2][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[C:12]=2[C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])[CH:5]=[CH:6][C:7]=1[O:31][CH3:32]
Reactant: C1CCNCC1
Reactant: CCCOC(=O)c1c(CBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Solvent: ClCCl
Product: CCCOC(=O)c1c(CN2CCCCC2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.9 %

Procedure:
A mixture of propyl 2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (1.5 g), piperidine (1.27 g) and dichloromethane (30 ml) was stirred at room temperature for 2 days. The reaction mixture was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-ethyl acetate (10:1, v/v) gave propyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-piperidinomethylquinoline-3-carboxylate (0.8 g, 53%). This compound was recrystallized from ethyl acetate - hexane. Colorless prisms, mp. 129°-131° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:36]=[C:37]([C:45]([F:47])([F:46])[F:48])[CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:40]=3)=[CH:32][CH:33]=2)[C:8]2[C:7](=[CH:12][CH:11]=[C:10]([Cl:25])[CH:9]=2)[CH:6]=1
Reactant: FC(F)(F)c1cc(Sc2ccc(Br)cc2)cc(C(F)(F)F)c1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc2)c1C
Yield: 27.5 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol), crude 1-(4-bromo-phenylsulfanyl)-3,5-bis-trifluoromethyl-benzene (0.334 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to provide {4-[4-(3,5-bis-trifluoromethyl-phenylsulfanyl)-phenyl]-6-chloro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.083 g, 27%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([C:15]2[CH:16]=[C:17]([CH3:27])[C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:19][CH:20]=2)[CH2:14][CH2:13]1>>[CH:12]1([C:15]2[CH:16]=[C:17]([CH3:27])[C:18]([N:21]3[CH2:22][CH2:23][N:24]([C:4]([C:3]4[CH:7]=[CH:8][C:9]([Br:11])=[CH:10][C:2]=4[Br:1])=[O:6])[CH2:25][CH2:26]3)=[N:19][CH:20]=2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1ccc(Br)cc1Br
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2Br)CC1
Yield: 69.4 %

Procedure:
Using 2,4-dibromobenzoic acid (530 mg) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (413 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Preparation Example 118, the title compound (630 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCCCC1

Procedure:
Using analogous procedures to those described in Note [33] immediately above, 1-(tert-butoxycarbonyl)-L-proline was reacted with piperidine to give (2S)-1-(tert-butoxycarbonyl)-2-piperidinocarbonylpyrrolidine which was deprotected and reacted with 2-bromoethanol. There was thus obtained the required starting material; NMR Spectrum: (CDCl3) 1.5-1.9 (m, 10H), 1.9-2.0 (m, 1H), 2.1-2.2 (m, 1H), 2.4-2.5 (m, 1H), 2.55-2.65 (m, 1H), 2.8-2.9 (m, 1H), 3.3-3.7 (m, 6H), 4.3 (br s, 1H); Mass Spectrum: M+H+ 227.
Reaction SMILES: [CH:1]1(/[C:4](=[N:6]/[S:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8])/[CH3:5])[CH2:3][CH2:2]1.[CH3:13][Al](C)C.[Li]C>C1(C)C=CC=CC=1>[CH:1]1([C:4]([NH:6][S:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8])([CH3:13])[CH3:5])[CH2:3][CH2:2]1
Reactant: C[Al](C)C
Reactant: C/C(=N\S(=O)C(C)(C)C)C1CC1
Agent: [Li]C
Solvent: Cc1ccccc1
Product: CC(C)(NS(=O)C(C)(C)C)C1CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 27.7 %

Procedure:
To a stirred solution of (E)-N-(1-cyclopropylethylidene)-2-methylpropane-2-sulfinamide (0.6 g, 3.2 mmol) in 30 mL of toluene at −78° C. was added Me3Al (1.76 mL, 3.5 mmol, 2M in toluene) under nitrogen atmosphere. After stirred 20 minutes at −78° C., MeLi (2.3 mL, 7 mmol, 3M in dimethoxymethane) was added drop-wise and the mixture stirred at −78° C. for 4 hours. The reaction was quenched by adding 2 mL of water. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (4:1, v/v) to give N-(2-cyclopropylpropan-2-yl)-2-methylpropane-2-sulfinamide (0.18 g, 28%) as a yellow oil. MS: (M+H)+=204.1; 1H NMR (300 MHz, CDCl3): δ 3.03 (brs, 1H), 1.17 (s, 3H), 1.16 (s, 9H), 1.12 (s, 3H), 0.98-0.95 (m, 1H), 0.43-0.29 (m, 4H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([C@@H:36]([O:38]C(=O)C)[CH3:37])=[O:35]>>[OH:38][C@@H:36]([CH3:37])[C:34]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:35]
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@H](N)CC3)c[nH]c12
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@H](NC(=O)[C@H](C)O)CC3)c[nH]c12

Procedure:
Starting from trans-4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A182) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH:13]([OH:20])[CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([O:20][CH:13]([CH2:14][N:15]1[CH2:16][CH2:17][CH2:18][CH2:19]1)[CH2:12][O:11][C:1]1[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: OC(COc1cccc2c1CC=CC2)CN1CCCC1
Product: CC(=O)OC(COc1cccc2c1CC=CC2)CN1CCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 3 g. of 1-(5,8-dihydro-1-naphthyloxy)-3-(pyrrolidino)-2-propanol, 1.5 g. of fused acetate and 15 ml. of acetic anhydride is heated on a steam bath with occasional shaking for one hour. At the end of this time, the warm solution is poured with vigorous stirring into 100 ml. of ice water. The mixture is stirred for 10-15 minutes and the crystals of 1-(5,8-dihydro-1-naphthyloxy)-3-(pyrrolidino)-2-propyl acetate are collected, washed thoroughly with water, and purified by crystallization from alcohol.
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[NH:15][C:14]2=[O:24])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[C:25](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[F:1][C:2]1[C:12]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[N:15]([CH3:25])[C:14]2=[O:24])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C1COc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc2N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc3c(cc2F)OCC(=O)N3)c1=O
Reaction time: 4 h
Yield: 119.9 %

Procedure:
0.85 g of 3-(7-fluoro-3-oxo-2H-1,4-benzoxazin-6-yl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione was dissolved in 8.5 ml of N,N-dimethylformamide. Then 0.17 g of anhydrous potassium carbonate and 0.15 ml of methyl iodide were added and the mixed solution was stirred for 4 hours. After the reaction was completed, N,N-dimethylformamide was distilled off and the residue was extracted with ethyl acetate by adding water. The extract was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then ethyl acetate was distilled off to obtain a crude product. This product was purified by column chromatography using chloroform as developing solvent to yield 0.53 g of the objective compound as pale yellow crystals.