Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)([N:16]1[CH:20]=[CH:19]N=C1)=O.C(N(CC)CC)C.C(N)C>C1COCC1>[CH2:20]([NH:16][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[Cl:1])[CH3:19]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: CCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 1 h
Yield: 45.5 %

Procedure:
2-Chloro-5-nitrobenzoic acid (20 g, 100 mmol) in THF (200 mL) was treated with carbonyldiimidazole (CDI) (17.8 g, 110 mmol) and triethylamine (16 mL, 110 mmol) at room temperature. After 1 hr, a solution of ethylamine (70% in water, 10 mL) was added and the mixture was stirred for 18 h. Solvent was removed by evaporation and the residue was dissolved in methylene chloride, washed with 3% KOH solution followed by water (three times) until the aqueous phase extracts were colorless. The organic phase was dried over MgSO4, filtered, and the filtrate was concentrated to provide 10.4 g of N-ethyl-2-chloro-5-nitrobenzamide as light yellow crystals.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[Cl:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[C:33]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[CH:32]=[CH:31]2>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:41]2[CH2:42][CH2:43][N:38]([C:33]3[CH:32]=[CH:31][C:30]4[C:35](=[CH:36][CH:37]=[C:28]([Cl:27])[CH:29]=4)[N:34]=3)[CH2:39][CH2:40]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Clc1ccc2nc(N3CCNCC3)ccc2c1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc4cc(Cl)ccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 6-chloro-2-piperazin-1-yl-quinoline.
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[C:5]([F:10])=[CH:6][CH:7]=[CH:8][CH:9]=1.[NH:21]([CH3:46])[C@H:22]([C:26]([N:28]([CH3:45])[C@H:29]([C:42]([NH2:44])=[O:43])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:32]=1)=[O:27])[CH:23]([CH3:25])[CH3:24].O>C1COCC1>[NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([N:21]([CH3:46])[C@H:22]([C:26]([N:28]([CH3:45])[C@H:29]([C:42]([NH2:44])=[O:43])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C:38]([CH3:41])([CH3:39])[CH3:40])[CH:32]=1)=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:13])[CH2:3][C:4]1[C:5]([F:10])=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1F)C(=O)O
Reactant: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccccc1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a solution of Boc-Phe(2-F)-OH (0.20 g, 0.706 mmol), N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.21 g, 0.578 mmol) and CMPI (0.20 g, 0.783 mmol) in THF (6 ml), TEA (0.30 ml, 2.15 mmol) was added under cooling with ice and stirred at room temperature overnight. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol:aqueous ammonia=60:1:0.05) to give Boc-Phe(2-F)-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.33 g, 91%).
Reaction SMILES: [CH3:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[CH2:16][C:17]1[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=1>>[CH2:26]([O:25][C:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:13][CH:12]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)c1ccccc1CBr
Reactant: CCOC(=O)C(C)c1ccc(O)cc1
Product: CCOC(=O)c1ccccc1COc1ccc(C(C)C(=O)OCC)cc1

Procedure:
Reaction of ethyl α-methyl-p-hydroxyphenylacetate with ethyl α-bromo-o-toluate by the method described in Example 1b provides ethyl 4-(2-ethoxycarbonylbenzyloxy)-α-methylphenylacetate as a clear oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[CH2:17][CH:18]=[CH:19][C:20]1[CH:72]=[C:23]2[N:24]=[C:25]([CH3:71])[C:26]([C@H:60]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])[C:61]([O:63][CH2:64][CH3:65])=[O:62])=[C:27]([N:28]3[CH2:33][CH2:32][C:31]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][C@H:40]([O:42][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)[CH3:41])([CH3:34])[CH2:30][CH2:29]3)[N:22]2[N:21]=1)C1C=CC=CC=1.[H][H].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(O)C.C1COCC1.[Pd]>[C:67]([O:66][C@@H:60]([C:26]1[C:25]([CH3:71])=[N:24][C:23]2[N:22]([N:21]=[C:20]([CH2:19][CH2:18][CH2:17][C:10]3[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=3[OH:8])[CH:72]=2)[C:27]=1[N:28]1[CH2:33][CH2:32][C:31]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][C@H:40]([OH:42])[CH3:41])([CH3:34])[CH2:30][CH2:29]1)[C:61]([O:63][CH2:64][CH3:65])=[O:62])([CH3:68])([CH3:69])[CH3:70]
Reactant: [H][H]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=CCc3cc(F)c(F)cc3OCc3ccccc3)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(CCCc3cc(F)c(F)cc3O)nn2c1N1CCC(C)(OCCCC[C@@H](C)O)CC1
Yield: 66.3 %

Procedure:
To a solution of (S)-ethyl 2-(2-(3-(2-(benzyloxy)-4,5-difluorophenyl)prop-1-en-1-yl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (190 mg, 0.190 mmol) in ethanol (4 mL) was added 10% Pd—C (60.6 mg, 0.057 mmol) and the resulting mixture was stirred under balloon hydrogen atmosphere for 16 h. At this point LCMS indicates completion of reaction. Mixture was then filtered through a pad of celite, concentrated and dried under high vacuum. The residue was then treated with 1M TBAF (0.949 mL, 0.949 mmol) in THF (4 mL) for 16 h. Mixture was then concentrated and purified by Biotage (5-70% EtOAc/hexane) to afford to afford (S)-ethyl 2-(tert-butoxy)-2-(2-(3-(4,5-difluoro-2-hydroxyphenyl)propyl)-7-(4-(((R)-5-hydroxyhexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (85 mg, 0.126 mmol, 66.4% yield) as thick paste. 1H NMR (500 MHz, CDCl3) 6.96-6.89 (m, 1H), 6.68 (dd, J=11.7, 7.1 Hz, 1H), 6.34 (s, 1H), 5.90 (br. s., 1H), 4.31-4.09 (m, 2H), 3.93-3.81 (m, 1H), 3.44 (br. s., 2H), 2.88-2.70 (m, 4H), 2.63 (s, 4H), 2.12-1.94 (m, 4H), 1.90 (br. s., 2H), 1.57-1.42 (m, 6H), 1.41-1.31 (m, 3H), 1.27-1.18 (m, 18H). LCMS (M+H)=675.6.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:25])[C:8]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=3)=[C:9]([S:13][CH3:14])[O:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:25])[C:8]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)=[C:9]([S:13][CH3:14])[O:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(-c2c(SC)oc3cc(OC)ccc3c2=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CSc1oc2cc(O)ccc2c(=O)c1-c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.7 %

Procedure:
Methyl 4-(7-methoxy-2-(methylthio)-4-oxo-4H-chromen-3-yl)benzoate (36 mg, 0.101 mmol) in dry dichloromethane (5.0 mL) was cooled to 0° C. under nitrogen and BBr3 in DCM (1.0 M, 0.2 mL, 0.202 mmol) was added rapidly. Then the mixture was stirred at room temperature overnight. The reaction was quenched with water and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford Example 11 as an off-white solid (8.2 mg, 25%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[BrH:36].[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([Br:36])=[C:12]2[CH2:18][CH2:19][N:20]1[C:21](=[O:30])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]1=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: Br
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1CCc1c(Br)[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 0 °C

Procedure:
To a solution of 2-[2-(5-benzyloxy-1H-indol-3-yl)ethyl]isoindole-1,3-dione (800 mg in a mixture of dry 25 mL tetrahydrofuran and 25 mL dry chloroform) at 0° C. was added pyridinium hydrobromide perbromide (666 mg) and the mixture stirred at 0° C. After 23 minutes the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate. The organic portion was washed with saturated sodium bicarbonate (3×) and 0.3M sodium bisulfate (3×) then dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane:ethyl acetate, 7:2) followed by repurification by flash chromatography on silica gel (methylene chloride) gave the title compound (632 mg).
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[CH2:23]([NH:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ClCc1ccccc1
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: c1ccc(CNCC(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
To a solution of 2,2-diphenyl ethyl amine (10.0 g, 0.051 mol) and triethyl amine (20.5 g, 0.203 mol) in 200 mL tetrahydrofuran was added a solution of benzyl chloride (7.1 g, 0.056 mol) in 100 mL tetrahydrofuran. The reaction mixture was heated to reflux for 48 hours, then cooled to room temperature and concentrated in vacuo. The residue was taken up in 300 mL chloroform and washed with 3×100 mL water. The organic layer was then stirred with 100 mL 2N NaOH solution for 30 minutes. The layers were separated and the aqueous layer was extracted further with 2×100 mL chloroform. The chloroform layers were combined, dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting oil was further purified by chromatography, eluting with hexane/ethyl acetate. 5.8 g of a clear oil was isolated which was characterized by analytical and spectroscopic properties as the hydrochloride salt, mp 250-253° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:16]4[C:17]=3[C:12](=[CH:13][CH:14]=[CH:15]4)[N:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.Cl.N1(CCCNC2C3C=CC=C4C=3C(=CC=C4)N=2)C=CN=C1.[C:45](Cl)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[N:11]1[C:12]2[C:17]3[C:16](=[CH:21][CH:20]=[CH:19][C:18]=3[C:10]=1[N:9]([CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[C:45](=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH:15]=[CH:14][CH:13]=2
Reactant: c1cc2c3c(cccc3c1)C(NCCCn1ccnc1)=N2
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(c1ccccc1)N(CCCn1ccnc1)C1=Nc2cccc3cccc1c23
Temperature: 25 °C
Reaction time: 4 h
Yield: 14.5 %

Procedure:
Five grams of N-(3-(1H-imidazol-l-yl)propyl)benz(cd)indole-2-amine (the free base of the compound of Example 1) and 100 mg of 4-dimethylaminopyridine were dissolved in 50 ml of pyridine. The solution was stirred as 2.8 grams of benzoyl chloride was slowly added. An exotherm was noted. The mixture was stirred at room temperature for 4 hours and then drowned onto 500 ml of ice. The precipitated solid was collected, washed with water, and dried. Recrystallization from chloroform-hexane gave 1.0 gram of desired compound, mp 148° C.-153° C., with decomposition.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](I)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C([Mg]Cl)(C)C.CN(C)[CH:18]=[O:19]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[O:19])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CN(C)C=O
Reactant: Cn1cc(F)cc(I)c1=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cn1cc(F)cc(C=O)c1=O
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
5-Fluoro-3-iodo-1-methyl-1H-pyridin-2-one (32, 120.5 g, 476 mmol) was dissolved in 2381 mL of tetrahydrofuran and cooled to −40° C. in a dry ice acetone bath. Isopropylmagnesium chloride (310 mL, 619 mmol) was added dropwise and the mixture was stirred for 30 minutes. Then 92 mL of N,N-dimethylformamide was added and the mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched by adding 200 mL of 10% aqueous hydrochloric acid, then concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 100% ethyl acetate. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a yellow solid (33, 35 g, 226 mmol, 47.4%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[F:1][C:2]1[CH:3]=[C:4]([S:8][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:22][C:23]3[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=3)[N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: Fc1cccc(S)c1
Product: COc1ccc2c(Sc3cccc(F)c3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 305 was used, starting from 3-fluoro-benzenethiol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(3-fluoro-phenylsulfanyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 381 (MH+).
Reaction SMILES: Cl.[C:2]([O:10][C@@H:11]1[C@@H:15]([CH2:16][OH:17])[CH2:14][C@@H:13]([NH2:18])[C@@H:12]1[O:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1.[Cl-].[NH4+]>C(Cl)Cl>[C:20]([O:19][C@H:12]1[C@H:13]([NH:18][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH2:14][C@H:15]([CH2:16][OH:17])[C@H:11]1[O:10][C:2](=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: O=C(N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccncc1
Reaction time: 0.33 h
Yield: 60 %

Procedure:
A solution of (1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diyl dibenzoate hydrochloride (150. mg, 0.380 mmol) in DCM (10.0 mL) at 0° C. was treated with EtN (0.170 mL, 1.22 mmol) and stirred for 20 min. Isonicotinoyl chloride (88.0 mg, 0.490 mmol) was then added and the mixture was stirred for 2 h. The reaction was treated with saturated aqueous solution of ammonium chloride (50 mL) and extracted with DCM (2×50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to afford the title compound (100. mg, 60%). LC/MS: Rt=1.49 min, ES+ 461 (FA standard).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OCC(Cl)(Cl)Cl)=O)[CH2:10][CH:9]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:4][CH:3]=1>C(O)(=O)C.O.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:4][CH:3]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCC(c2ccc(Cl)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc(C2CCNCC2OCc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.6 %

Procedure:
A suspension of 0.420 g (0.8 mmol) of 2,2,2-trichloroethyl 4-(4-chloro-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate and 300 mg of zinc in 10 ml of acetic acid was stirred at room temperature for 12 hours. The reaction solution was diluted with 40 ml of water and extracted four times with 30 ml of methylene chloride. The organic phase was washed twice with 40 ml of 1N sodium hydroxide solution each time, dried over sodium sulphate, filtered and evaporated. The residue was chromatographed on silica gel using a 9:1 mixture of methylene chloride and methanol as the eluent. There was obtained 0.210 g (74% of theory) of (3RS,4RS)-4-(4-chloro-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine, MS: 210 (M-C11H9)+, which was converted into the hydrochloride of m.p. 159-161° C. (dec.) with a solution of hydrogen chloride in methanol.
Reaction SMILES: Cl.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:9]2[CH2:14][CH:13]([C:15]3[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[N:17][S:18][N:19]=3)[CH2:12][N:11]=[CH:10]2)C=CC=CC=1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>>[F:43][C:42]([F:45])([F:44])[C:40]([OH:46])=[O:41].[CH2:21]([O:20][C:16]1[C:15]([CH:13]2[CH2:14][NH:9][CH:10]=[N:11][CH2:12]2)=[N:19][S:18][N:17]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCOc1nsnc1C1CN=CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCOc1nsnc1C1CN=CNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
1-Triphenylmethyl-5(3(1-n-heptanoxy)-1,2,5-thiadiazol-4-yl)-1,4,5,6-tetrahydropyrimidine HCl (580 mg, 1 mmol) is dissolved in TFA (11 ml) and stirred overnight at room temperature. The TFA is evaporated and the resulting dark oil triturated with ether. After decanting the ether, the remaining solids are recrystallized from methanol/ether to give 344 mg (87%) white crystals identified by 300 MHz nmr, ms m/z=360.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:20])[CH:5]=[C:6]2[C:11]=1[N:10]([C@@H:12]1[CH2:14][C@@H:13]1[F:15])[CH:9]=[C:8]([C:16]([OH:18])=[O:17])[C:7]2=[O:19].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH2:32][C@H:31]2[CH2:35][NH:36][CH2:37][C@@H:30]12)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>C(#N)C>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH2:32][C@@H:31]2[C@H:30]1[CH2:37][N:36]([C:3]1[C:2]([Cl:1])=[C:11]3[C:6]([C:7](=[O:19])[C:8]([C:16]([OH:18])=[O:17])=[CH:9][N:10]3[C@@H:12]3[CH2:14][C@@H:13]3[F:15])=[CH:5][C:4]=1[F:20])[CH2:35]2)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]2CNC[C@H]21
Reactant: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2c(Cl)c(F)c(F)cc2c1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]2CN(c3c(F)cc4c(=O)c(C(=O)O)cn([C@@H]5C[C@@H]5F)c4c3Cl)C[C@H]21
Yield: 55.9 %

Procedure:
In 20 ml of acetonitrile were dissolved 344 mg of 8-chloro-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 490 mg of (S,S)-1-t-butoxycarbonyloctahydropyrrolo[3.4-b]pyridine (also termed "(S,S)-2-t-butoxycarbonyl-2,8-azabicyclo[4.3.0]nonane"), and 1 ml of triethylamine, and the solution was heated under reflux for 5 hours. After completion of the reaction, the solvent was removed under reduced pressure. To a residue was added 30 ml of water, followed by extracting with chloroform (30 ml×4). The combined organic layer was washed with 100 ml of a 10% citric acid aqueous solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and a residue was recrystallized from acetonitrile to yield 317 mg of the titled compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:29])=[C:8]([CH2:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH:9]=1)=[O:4].FC(F)(F)C(O)=O>O1CCCC1>[F:28][CH:26]([F:27])[O:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[CH:15]=[CH:14][C:13]([N:11]([CH2:10][C:8]3[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[O:6][C:7]=3[CH3:29])[CH3:12])=[CH:18][CH:17]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc(CN(C)c2ccc(-c3ccc(OC(F)F)cc3)cc2)c(C)o1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1oc(C(=O)O)cc1CN(C)c1ccc(-c2ccc(OC(F)F)cc2)cc1
Reaction time: 30 h
Yield: 17.7 %

Procedure:
A solution of 4-{[(4′-difluoromethoxy-biphenyl-4-yl)-methyl-amino]-methyl}-5-methyl-furan-2-carboxylic acid methyl ester (175) (30 mg, 0.07 mmoles) in dry tetrahydrofuran (20 ml) was treated with potassium trimethylsilanoate (19 mg, 0.15 mmoles) and the mixture stirred under an argon atmosphere for 30 hours. Trifluoroacetic acid was added until the pH=2. After evaporation of the solvent, the residue was purified by HPLC to afford compound 176 (4.8 mg) as a white solid. LC/MS System D; Rt=9.42 mins, m/z (ES+)=388 (M+H for C21H19F2NO4).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:7][CH:8]=1.[NH2:20][C:21]1[C:25]([C:26]#[N:27])=[CH:24][NH:23][N:22]=1>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]3[N:23]=[CH:24][C:25]([C:26]#[N:27])=[C:21]3[N:20]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1cccc(C(F)(F)F)c1
Reactant: N#Cc1c[nH]nc1N
Product: N#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Yield: 42.4 %

Procedure:
Reaction of 1-(3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (284 mg, 1.0 mmol), prepared from commercially available 3-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a white solid (151 mg, 42%). MS (ISP) 357.0 [(M+H)+]; mp 192° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.[C:13](OC(=O)C)(=[O:15])[CH3:14]>CO>[OH:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][CH:3]=[C:2]2[NH:1][C:13](=[O:15])[CH3:14])=[CH:7][CH:8]=1
Reactant: Nc1cccc2ccc(O)cc12
Reactant: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)Nc1cccc2ccc(O)cc12
Temperature: 25 °C
Yield: 93.2 %

Procedure:
To a solution of 8-amino-2-naphthol (149.1 g, 0.937 mol) in methanol (1 L) was added acetic anhydride (93 mL, 0.984 mol). The reaction was refluxed for 90 minutes and cooled to room temperature. The solvent was removed and the residue was filtered through a plug of silica with ethyl acetate. The solvent was removed to yield 175.8 g (93%) of the title compound as a dark purple solid. An analytical sample was further purified by reverse phase preparative HPLC to yield a pink solid: mp 161–162° C.; 1H NMR (DMSO-d6):δ 2.15 (3H, s), 7.09 (1H, dd, J=1.95 Hz, J=8.79 Hz), 7.20–7.26 (2H, m), 7.49 (1H, d, J=7.31 Hz), 7.63 (1H, d, J=8.11 Hz), 7.77 (1H, d, J=8.81 Hz), 9.76 (1H, s), 9.79 (1H, s); MS (ESI) m/z 202 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[C:12]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:28]1([S:31](Cl)(=[O:33])=[O:32])[CH2:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[C:12]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][S:31]([CH:28]4[CH2:30][CH2:29]4)(=[O:33])=[O:32])[CH3:20])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: C[C@H](N)[C@H](Oc1cccc2c1cnn2-c1ccc(F)cc1)c1ccccc1
Product: C[C@H](NS(=O)(=O)C1CC1)[C@H](Oc1cccc2c1cnn2-c1ccc(F)cc1)c1ccccc1

Procedure:
Prepared according the protocol described for Example 1 using (1R,2S)-1-[1-(4-fluorophenyl)indazol-4-yl]oxy-1-phenyl-propan-2-amine (3a, 30 mg, 0.08 mmol) and cyclopropylsulphonyl chloride (22 μl, 0.21 mmol). Yield: 20 mg (53%).