Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][CH:3]=1.Cl.[NH:13]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])N>C(O)C.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3[C:23]4[C:15](=[C:16]([C:17]([OH:19])=[O:18])[CH:20]=[CH:21][CH:22]=4)[NH:13][C:8]=32)=[CH:4][CH:3]=1
Reactant: NNc1ccccc1C(=O)O
Reactant: O=C1CCc2ccc(Br)cc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccc2c3c([nH]c12)-c1cc(Br)ccc1C3
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of 6-bromoindanone (0.447 g, 2.12 mmol) [Adamczyk, M. et al. J. Org. Chem. 1984, 49, 4226-4237] in ethanol (100 mL) was added a solution of 2-hydrazinobenzoic acid hydrochloride (0.800 g, 4.24 mmol) in deionized water (50 mL). The mixture was stirred for 1 h then cooled to 0° C. The precipitated hydrazone was vacuum filtered and dried in vacuo to afford 0.628 g (86%) of the title compound as a yellow solid: mp 186° C. (dec).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH2:10][C:11]#[CH:12])=[O:8])[C@H:3]1[C:13](OC(C)(C)C)=[O:14].[C:21]([C@@H:23]([OH:37])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:25]=1)#[N:22]>>[CH3:1][C:2]1([CH3:20])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH2:10][C:11]#[CH:12])=[O:8])[C@H:3]1[C:13]([O:37][C@H:23]([C:21]#[N:22])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:25]=1)=[O:14]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: C#CCOC(=O)/C=C\[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Product: C#CCOC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Yield: 116.6 %

Procedure:
Using the procedure of Step C of Example 13, 1.59 g of the product of Step A and 1.8 g of (S)α-cyano-3-phenoxy-benzyl alcohol were reacted and after 2 hours, the mixture was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 9-1 cyclohexane-ethyl acetate mixture yielded 2.86 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[Z-2-(propargyloxycarbonyl)-ethenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+44°±1.5° (c=1% in CHCl3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][NH2:16])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[C:27]1([S:37](Cl)(=[O:39])=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][NH:16][S:37]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)(=[O:39])=[O:38])[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CN)CC1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CNS(=O)(=O)c2cccc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of trans-(4-aminomethyl-cyclohexylmethyl) carbamic acid tert-butyl ester (17 g) and ethyldiisopropylamine (14.41 ml) in N,N-dimethylformamide (350 ml) is cooled to 0° C. and treated with a solution of naphthalene-1-sulfonylchloride (15.9 g) in N,N-dimethylformamide (100 ml). The reaction is stirred at ambient temperature for 2 h, concentrated in vacuo. The residue is taken up in dichloromethane, washed with a 0.5 N HCl solution, a saturated aqueous sodium carbonate solution and water, dried and concentrated. Crystallization from hexanes-ethyl acetate gives trans-{4-[(naphthalene-1-sulfonylamino)-methyl]cyclohexylmethyl}-carbamic acid tert-butyl ester as a white powder, melting at 199-200° C. Rf (A1) 0.42.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([C:9]([O:11]CC)=[O:10])[O:6][N:5]=1)([CH3:3])[CH3:2].O[NH:15]/[C:16](=N/[H])/[C:17]1C=CC=NC=1.[OH-].[Na+]>>[N:15]1[CH:16]=[CH:17][CH:2]=[C:1]([C:4]2[N:8]=[C:7]([C:9]([OH:11])=[O:10])[O:6][N:5]=2)[CH:3]=1
Reactant: CCOC(=O)c1nc(C(C)C)no1
Reactant: [H]/N=C(/NO)c1cccnc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1nc(-c2cccnc2)no1

Procedure:
Following the procedure described in U.S. Pat. No. 5,578,550 for the preparation of ethyl 3-isopropyl-1,2,4-oxadiazole-5-carboxylate, the title product was prepared from (E)—N-hydroxynicotinimidamide (2.727 g, 19.88 mmol) and ethyl oxalyl chloride (2.89 mL, 25.9 mmol) followed by subsequent ester hydrolysis with sodium hydroxide solution according to Example 225(b). Yield 1.32 g. 1H NMR (400 MHz; d6-DMSO): δ 7.63 (m, HA), 8.32 (m, 1H), 8.86 (dd, 1H), 9.03 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]Cl.[N-:11]=[N+:12]=[N-:13].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][N:11]=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCc1ccc(Cl)c(Cl)c1

Procedure:
A stirred mixture of 3,4-dichlorobenzyl chloride (12.6 g, 64.5 mmol) and sodium azide (7.0 g, 0.11 mole) in absolute ethanol (70 ml) was refluxed for 4.75 hours, cooled and filtered to provide a solution of 3,4-dichlorobenzyl azide. Separately, 2-cyanoacetamide (5.5 g, 65 mmol) was added to a 35° C. solution of sodium (1.5 g, 65 mmol) in absolute ethanol (125 ml), and to the resulting suspension was added the above azide solution dropwise over 10 minutes. The combined mixtures were refluxed for 1 hour, kept 16 hours at ambient temperature and 1 hour at 5° C., and filtered. The crude product was dried under vacuum, dissolved in boiling ethanol (290 ml), filtered hot, and cooled to 0° C. The solid was collected by filtration and dried under vacuum to provide 12.4 g (67%) of 1-(3,4-dichlorobenzyl)-5-amino-1,2,3-triazole-4-carboxamide, m.p. 221°-222° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH3:17])[CH:8]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:24]([O-])([N+]([O-])=O)=[O:25]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:24]=[O:25])[C:5]([N:7]([CH3:17])[CH:8]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 70.2 %

Procedure:
2.7 g of 1-(2-chloroethyl)-3-methyl-3-D-ribofuranosylurea are dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.1 g of 1-(2-chloroethyl)-1-nitroso-3-methyl-3-ribofuranosylurea are thereby obtained as a yellow powder.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]#[C:16][CH3:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[O:20]1[CH2:24]CC[CH2:21]1>>[CH3:21][O:20][CH2:24][N:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]#[C:16][CH3:17])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC#Cc1cc(C)nc(Nc2ccccc2)n1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CC#Cc1cc(C)nc(N(COC)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
2-Anilino-4-methyl-6-(1-propynyl)pyrimidine (2.2 g) was added to a suspension in 50 ml of tetrahydrofuran of 0.5 g of sodium hydride (60%) of which oily component was removed with n-hexane, and the mixture was stirred for 30 minutes at 50°-55° C. After cooling to room temperature, 1.0 g of chloromethyl methyl ether was added to the mixture and stirred for 3 hours. The reaction mixture was poured into water and extracted with 150 ml of toluene. the toluene layer was washed with water, dried over Glauber's salt and concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.7 g (yield: 63%) of 2-(N-methoxymethylanilino)-4-methyl-6-(1-propynyl)pyrimidine.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[C:43](=[O:47])[NH:42][CH2:41][CH2:40]3)O1>>[F:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:37]3[CH:38]=[C:39]4[C:44](=[CH:45][CH:46]=3)[C:43](=[O:47])[NH:42][CH2:41][CH2:40]4)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Reactant: CC1(C)OB(c2ccc3c(c2)CCNC3=O)OC1(C)C
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc5c(c4)CCNC5=O)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (Example 8, Step 1). LCMS (M+H)+=437.2.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([OH:13])[CH:3]=1.C1C(=O)N([Cl:21])C(=O)C1.Cl.[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C.O>[Cl:21][C:3]1[C:4]([OH:13])=[N:5][CH:6]=[C:7]([C:2]=1[OH:1])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cnc(O)cc1O
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc(O)c(Cl)c1O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.9 %

Procedure:
To a solution of ethyl 4,6-dihydroxynicotinate (1.0 g, 5.43 mmol) in DMF (10 mL) was added NCS (797 mg, 5.96 mmol) and conc. HCl (0.05 mL). After stirring at room temperature for 2.5 h, it was added water and Na2S2O3, the precipitate was collected by filtration, washed with 1N HCl and dried to give ethyl 5-chloro-4,6-dihydroxynicotinate (920 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:45])[O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:45])[O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: NCCCN1CCC(c2cccc(NC(=O)OCc3ccccc3)c2)CC1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Product: O=C(Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1)OCc1ccccc1

Procedure:
Example 141 was prepared from bis(4-fluorophenyl)acetic acid and benzyl 3-[1-(3-amino propyl)-4-piperidinyl]phenylcarbamate according to the procedures described in Scheme 9: ESMS m/e: 598.5 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.[CH3:13][C:14](=[CH2:16])[CH3:15].C([O-])(O)=O.[Na+]>O>[C:14]([O:8][C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9])([CH3:16])([CH3:15])[CH3:13]
Reactant: C=C(C)C
Reactant: O=C(O)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.8 %

Procedure:
To a solution of cyclohexanecarboxylic acid (10.0 g, 78 mmol) in DCM (75 mL) concentrated sulfuric acid (765 mg, 7.8 mmol) was added. At a temperature between −15° C. and −10° C. isobutylene (10.94 g, 195 mmol) was introduced over 1 h. The cooling bath was removed and the reaction mixture was stirred at room temperature for 72 h. Then a second portion of isobutylene (10.94 g, 195 mmol) was introduced over 1 h at −10° C. The reaction mixture was stirred at room temperature for an additional 20 h, then NaHCO3 (7.864 g, 93.6 mmol) was added before the mixture was stirred at room temperature for another 1 h. Water (50 mL) was added under stirring. After 45 min the reaction mixture was worked up and washed until neutral. The organic phases were combined, dried over sodium sulfate and concentrated on a rotary evaporator. The crude product (13.5 g) was distilled over a Vigreux column at 35° C. (0.04 mbar) to afford 10.9 g (76%) cyclohexanecarboxylic acid tert-butyl ester as a colorless oil. 1H-NMR (CDCl3, 400 MHz): ppm 1.12-1.54 (m, 14H), 1.55-1.99 (m, 5H), 2.12-2.22 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.CCN(C(C)C)C(C)C.[F:28][C@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:31]2[CH2:32][CH2:33][C@H:29]([F:28])[CH2:30]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: F[C@H]1CCNC1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(C2CCc3c2nc(Cl)nc3N2CC[C@H](F)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (135 mg, 0.477 mmol) in MeOH (4768 μL) was added DIPEA (208 μL, 1.192 mmol), then (S)-3-fluoropyrrolidine (46.7 mg, 0.524 mmol). The reaction was allowed to stir at ambient temperature for 2 h. The solvent was removed and the residue applied to Silica gel and eluted with an EtOAc/Hex gradient to afford two diasteriomers (Hp1 and Hp2). Hp1: LC-MS (M+H)+=336.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.06-7.13 (2H, m), 6.93-7.00 (2H, m), 5.32 (1H, td, J=52.57, 3.17 Hz), 4.17 (1H, dd, J=9.16, 5.49 Hz), 4.06-4.14 (1H, m), 3.98-4.06 (1H, m), 3.76-3.90 (2H, m), 3.25 (1H, ddd, J=15.11, 8.55, 6.26 Hz), 3.08-3.16 (1H, m), 2.51-2.60 (1H, m, J=13.20, 9.12, 9.12, 6.41 Hz), 2.32-2.42 (1H, m), 2.00-2.17 (2H, m). Hp2: LC-MS (M+H)+=336.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.06-7.14 (2H, m), 6.94-7.02 (2H, m), 5.25-5.40 (1H, m), 3.99-4.24 (3H, m), 3.75-3.92 (2H, m), 3.19-3.28 (1H, m), 3.10-3.19 (1H, m), 2.57 (1H, dddd, J=13.24, 8.74, 8.55, 4.58 Hz), 2.31-2.43 (1H, m), 1.94-2.17 (2H, m)
Reaction SMILES: [CH3:1][C:2]1[C:8]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>CCOC(C)=O>[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[C:8]([B:9]3[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]3)[C:2]=2[CH3:1])=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)c2ccc(F)cc2)cccc1B1OC(C)(C)C(C)(C)O1
Reaction time: 22 h

Procedure:
A solution of 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (Intermediate 50-1, 1.10 g, 4.72 mmol) in EtOAc (25 mL) was treated with TEA (0.789 mL, 5.66 mmol), then with 4-fluorobenzoyl chloride (0.577 mL, 4.81 mmol) and the mixture was stirred at rt. After 22 h, the mixture was diluted with EtOAc, washed twice with water, then with brine, and dried and concentrated to provide 4-fluoro-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide as a glassy foam (1.705 g, ca. 90% purity, 92%). 1H NMR (400 MHz, chloroform-d) δ 7.96 (d, J=7.5 Hz, 1H) 7.90 (dd, J=8.6, 5.3 Hz, 2H) 7.66 (dd, J=7.4, 1.2 Hz, 1H) 7.63 (br. s., 1H) 7.22-7.29 (m, 1H) 7.18 (t, J=8.6 Hz, 2H) 2.53 (s, 3H) 1.36 (s, 12H). Mass spectrum m/z 356.1 (M+H)+.
Reaction SMILES: Cl[C:2]([N:4]1[C:8]([S:9][CH3:10])=[CH:7][C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:5]1)=[O:3].[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16].O>C1C=CC=CC=1>[CH2:15]([N:17]([CH2:18][CH3:19])[C:2]([N:4]1[C:8]([S:9][CH3:10])=[CH:7][C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:5]1)=[O:3])[CH3:16]
Reactant: CSc1cc(C(C)(C)C)nn1C(=O)Cl
Reactant: CCNCC
Solvent: O
Solvent: c1ccccc1
Product: CCN(CC)C(=O)n1nc(C(C)(C)C)cc1SC

Procedure:
To a stirred solution of 1-chlorocarbonyl-3-tert-butyl-5-(methylthio)pyrazole (23 g) in benzene (200 ml) at room temperature was added dropwise diethylamine (16 g, 23 ml). A white precipitate formed rapidly. The reaction mixture was refluxed (at 80°) for two hours, allowed to cool, and water (100 ml) added. The organic layer was washed once again with water, separated, dried and evaporated to give 1-(diethylcarbamoyl)-3-t-butyl-5-(methylthio)pyrazole. Recrystallisation from petrol gave the pure compound (16.5 g, 59% yield), of melting point 55°-6°.
Reaction SMILES: [Na].[NH2:2][C:3]1[N:8]=[C:7]([N:9]=O)[N:6]=[C:5]([NH2:11])[C:4]=1[NH2:12].[OH:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][CH:18]=1.O>C(OCCO)C>[NH2:9][C:7]1[N:6]=[C:5]([NH2:11])[C:4]2[C:3](=[N:2][C:24]([NH2:25])=[C:23]([C:20]3[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH2:14][OH:13])=[CH:22][CH:21]=3)[N:12]=2)[N:8]=1
Reactant: Nc1nc(N=O)nc(N)c1N
Reactant: N#CCc1ccc(OCCO)cc1
Agent: [Na]
Solvent: CCOCCO
Solvent: O
Product: Nc1nc(N)c2nc(-c3ccc(OCCO)cc3)c(N)nc2n1

Procedure:
460 mg metallic sodium were dissolved while stirring in 150 ml 2-ethoxyethanol. Thereafter to it was added while stirring 3.1 g (0.02 mole) of triamino-nitrosopyrimidine and 2.5 g (0.02 mole) p-(2-hydroxyethoxy)-phenyl acetonitrile and the mixture was stirred and heated in the water bath at 60° C. The color of the mixture changed from violet to light brown. After 14 hours of stirring, the reaction was stopped. The mixture is then allowed to cool. Unreacted 2,4,6-triamino-nitrosopyrimidine is filtered and the clear solution is evaporated and its volume reduced. The precipitate was taken up in hot acetone and by addition of petroleum ether, the raw product precipitated. The purification consisted of one recrystallization in butanol and also by passage through a silica gel column (Kieselgel 60, Merck). The title compound is obtained as yellowish-brown crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH:32]1(O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(O)cc3)oc2C)cc1
Reactant: OC1CCCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(OC4CCCCC4)cc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.4 %

Procedure:
To a 0° C. solution of 2-(4-{2-[2-(4-hydroxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy)-phenoxy}-2-methyl-propionic acid ethyl ester (0.60 g, 1.41 mmol), cyclohexanol (0.212 g, 2.11 mmol) and triphenyl phosphine (0.55 g, 2.10 mmol) in THF (18 mL) was added diisopropyl azodicarboxylate (0.43 g, 2.12 mmol) in THF (2 mL). The reaction was warmed to room temperature and stirred under N2 for 18 h. Silica gel was added directly to the reaction mixture and the solvent removed in vacuo to absorb the crude product onto the silica gel. The crude product was then purified by flash chromatography (3/1 hexanes/EtOAc) to afford 0.339 g (47%) 2-(4-{2-[2-(4-cyclohexyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester. 1H NMR (500 MHz, CDCl3) δ 7.94-7.85 (m, 2H), 6.92 (d, 2H, J=9.0 Hz), 6.82-6.75 (m, 4H), 4.32-4.23 (m, 1H), 4.21-4.16 (m, 4H), 2.98-2.90 (m, 2H), 2.39 (s, 3H), 2.05-1.95 (m, 2H), 1.85-1.78 (m, 2H), 1.62-1.51 (m, 3H), 1.52 (s, 6H), 1.42-1.25 (m, 3H), 1.27 (t, 3H, J=7.23 Hz); MS (ES+) Calc'd for C30H38NO6: Found m/e 508.3 (M+1, 100%).
Reaction SMILES: [C:1]([O:9][C:10]1([CH2:13][O:14]S(C)(=O)=O)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]1[CH:21]=[C:22]([N:40](C2C=CC(F)=CC=2)[C:41]([C:43]2([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44]2)=[O:42])[CH:23]=[CH:24][C:25]=1[O:26][C:27]1[C:36]2[C:31](=[CH:32][C:33](O)=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[C:1]([O:9][C:10]1([CH2:13][O:14][C:33]2[CH:32]=[C:31]3[C:36]([C:27]([O:26][C:25]4[CH:24]=[CH:23][C:22]([NH:40][C:41]([C:43]5([C:46](=[O:47])[NH2:48])[CH2:45][CH2:44]5)=[O:42])=[CH:21][C:20]=4[F:19])=[CH:28][CH:29]=[N:30]3)=[CH:35][C:34]=2[O:37][CH3:38])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)ccnc2cc1O
Reactant: CS(=O)(=O)OCC1(OC(=O)c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc(NC(=O)C4(C(N)=O)CC4)cc3F)ccnc2cc1OCC1(OC(=O)c2ccccc2)CC1
Temperature: 45 °C
Yield: 69 %

Procedure:
To a mixture of 1-((methylsulfonyloxy)methyl)cyclopropyl benzoate (801 mg, 2.97 mmol) and N-(3-fluoro-4-(7-hydroxy-6-methoxy quinolin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (1 g, 1.98 mmol) in DMA (5 mL) were added Cs2CO3 (1.93 g, 5.94 mmol, Aladdin). The reaction was heated at 45° C. overnight. The solvent was then removed in vacuo, and the residual was diluted with CHCl3 (30 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residual was purified by a silica gel column chromatography (EtOAc) to afford the title compound as a light yellow solid (800 mg, 60%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]2=1.CCCCC.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]=2[C:6]2[C:14]1=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCc2[nH]c3c(F)cccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: O=C1CCCc2c1c1cccc(F)c1n2Cc1ccccc1
Reaction time: 0.33 h
Yield: 69.7 %

Procedure:
8-Fluoro-1,2,3,9-tetrahydro-4H-carbazol-4-one (2.23 g, 0.011 mol) is added to a slurry of pentane-washed NaH (0.59 g, 0.015 mol) in DMF (18 mL) and after stirring for 20 min, benzyl bromide (1.7 mL, 0.014 mol) is added. The mixture is stirred for 1 h at which time the mixture is partitioned between water and ethyl acetate. The combined organic layers are dried over sodium sulfate and concentrated to dryness. The resulting residue is chromatographed on silica gel (200 mL) using methanol/dichloromethane (1/99). The solids are then recrstallized from ethyl acetate/dichloromethane/hexane to give 2.25 g (70%) of the title compound; mp 183-184° C.; MS (ESI−) for C19H16FNO m/z 292.1 (M−H)−; IR (drift) 1639, 1631, 1495, 1459, 1434, 1359, 1246, 1219, 1193, 1125, 798, 789, 736, 730, 698 cm−1; 1H NMR (CDCl3) δ2.23, 2.58, 2.87, 5.51, 6.92, 7.03, 7.16, 7.29, 8.07. Anal. Calcd for C19H16FNO: C, 77.80; H, 5.50; N, 4.78. Found: C, 77.58; H, 5.59; N, 4.79.
Reaction SMILES: [C:1](=O)([O:12][C@@H:13]([CH3:18])[C:14]([F:17])([F:16])[F:15])[O:2]C1C=CC([N+]([O-])=O)=CC=1.[CH2:20]([N:27]1[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[CH2:20]([N:27]1[CH2:31][CH2:30][C@H:29]([NH:32][C:1](=[O:2])[O:12][C@@H:13]([CH3:18])[C:14]([F:17])([F:16])[F:15])[CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Solvent: ClC(Cl)Cl
Product: C[C@H](OC(=O)N[C@H]1CCN(Cc2ccccc2)C1)C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of 4-nitrophenyl (2S)-1,1,1-trifluoropropan-2-yl carbonate (2.20 g) in CHCl3 (30 ml) was added (3S)-1-benzylpyrrolidin-3-amine (1.39 g) at room temperature. The resulting mixture was refluxed for 2 hours and then cooled to room temperature. The mixture was purified with silica gel column chromatography (eluent:hexane/EtOAc=1/0˜0/1) to give (2S)-1,1,1-trifluoropropan-2-yl [(3S)-1-benzylpyrrolidin-3-yl]carbamate as a pale yellow oil.