Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([O:12][CH3:13])=[O:11].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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:14]1([C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][C:4]=3[C:3]=2[C:10]([O:12][CH3:13])=[O:11])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1c(Br)sc2c1CCC2
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: O
Solvent: C1COCCO1
Product: COC(=O)c1c(-c2ccccc2)sc2c1CCC2
Temperature: 90 °C
Reaction time: 15 h

Procedure:
To a suspension of methyl 2-bromo-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate, phenyl boronic acid, and Pd(PPh3)4 in dioxane was added a 2 M aqueous Na2CO3 solution, followed by stirring at 90° C. for 15 hours. Water was added thereto, and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane:EtOAc) to obtain methyl 2-phenyl-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate as a colorless liquid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C@@H:5]12[C:13](=[O:14])[O:12][C:10](=[O:11])[C@@H:6]1[CH2:7][CH2:8][CH2:9]2>ClCCCl>[CH3:9][C:5]([CH3:13])=[CH:6][C:10]([C@H:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[C:13]([OH:12])=[O:14])=[O:11]
Reactant: O=C1OC(=O)[C@@H]2CCC[C@H]12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(C)=CC(=O)[C@H]1CCC[C@H]1C(=O)O
Reaction time: 4 h

Procedure:
To a stirred suspension of 4.38 g. (32.86 mmole) of anhydrous aluminum chloride in 100 ml. of 1,2-dichloroethane at room temperature is added 2.30 g. (16.43 mmoles) of cis-1,2-cyclopentanedicarboxylic anhydride. Ethylene is then bubbled through the clear solution with stirring for four hours.
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:18]([CH:20]1[O:22][CH2:21]1)[Cl:19]>CCOCC>[CH2:1]([O:17][CH2:21][CH:20]([OH:22])[CH2:18][Cl:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: ClCC1CO1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCOCC(O)CCl
Yield: 75 %

Procedure:
Hexadecanol (10.0 g, 0.0412 mole) and stannic chloride (0.04 g, 0.16 mmoles) were heated to 60° C. Epichlorohydrin (3.82 g, 0.0412 moles (was added over 1 hour and the reaction conditions kept constant for another hour. The hot product was extracted with 5% aqueous HCl and ether. The ether was concentrated to a white solid product (yield=75%).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1.C([O-])([O-])=O.[K+].[K+]>CO.Cl>[F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCF)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: FCCN1CCNCC1
Temperature: 30 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
Crude 1,1-dimethylethyl 4-(2-fluoroethyl)-1-piperazinecarboxylate was dissolved in 40 mL of MeOH and 40 mL 37% HCl. Reaction was stirred for 1 h. Carefully neutralized with solid K2CO3 and concentrated in vacuo being careful not to heat the H2O bath past 30° C. The resulting residue was taken up in diethyl ether and the solids were filtered and washed with diethyl ether and DCM several times. Filtrate was concentrated in vacuo, again being careful not to heat the H2O bath past 30° C., to give desired product 1-(2-fluoroethyl)piperazine (5.2 g, 73% over 2 steps) which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.40-4.57 (m, 2H), 2.64-2.73 (m, 4H), 2.53-2.61 (m, 1H), 2.46-2.53 (m, 2H), 2.29-2.40 (m, 4H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH2:6][C:5]([CH3:10])([CH3:9])[C:4]=1[CH3:11]>C(O)C.[Ni]>[OH:1][CH2:2][C:3]1[CH:4]([CH3:11])[C:5]([CH3:10])([CH3:9])[CH2:6][CH2:7][CH:8]=1
Reactant: CC1=C(CO)C=CCC1(C)C
Agent: [Ni]
Solvent: CCO
Product: CC1C(CO)=CCCC1(C)C
Yield: 91.6 %

Procedure:
30.4 g of 1-hydroxymethyl-2,3,3-trimethyl-cyclohexa-1,5-diene were hydrogenated at 10°-12° in the presence of 1g of Raney-nickel in 300 ml of ethanol. 3.95 l of hydrogen were then absorbed within 2.5 h. A filtration followed by evaporation and distillation gave 28.2 g of 1-hydroxymethyl-2,3,3-trimethyl-cyclohex-6-ene. nD = 1.4862, d20 = 9.9447
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:18]1[S:22][C:21]2[CH:23]=[CH:24][C:25]([O:27]C(=O)C3C=CC=CC=3)=[CH:26][C:20]=2[CH:19]=1)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:18]1[S:22][C:21]2[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][C:20]=2[CH:19]=1)=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cc(OC(=O)c3ccccc3)ccc2s1
Agent: C[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cc(O)ccc2s1

Procedure:
To a suspension of 732 mg (1.5 mmol) benzoic acid 2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-benzo[b]thiophen-5-yl ester (3) in 30 ml methanol was added 1.0 ml of a 5.4M solution of NaOMe in methanol. After 3 h at room temperature the reaction solution was poured on 5% aqueous citric acid. Extraction with ethyl acetate, washing of the organic phase with brine. The organic phase was dried over sodium sulfate, the solvent was evaporated and the residue subjected to silica gel chromatography (petrolether/ethyl acetate 3:1). {2-[(5-Hydroxy-benzo[b]thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester (4) was recrystallized from ethyl acetate/diethyl ether to yield 546 mg (1.42 mmol) as colorless crystals, mp. 185° C. (decomp.).
Reaction SMILES: C([NH:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20])(=O)C.S(=O)(=O)(O)O>>[NH2:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20]
Reactant: CC(=O)Nc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: Nc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Reaction time: 0.75 h

Procedure:
Ten grams of 4-acetamido-3-nitrobenzophenone was added portion-wise to 40 ml. of sulfuric acid. The reaction temperature was moderated with a water bath. After stirring about 45 minutes the reaction mixture was carefully poured over ice. The precipitated product was filtered to yield 4-amino-3-nitrobenzophenone.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][N:26]1[C:30](=[O:31])[CH2:29][NH:28][C:27]1=[O:32]>>[CH3:25][N:26]1[C:30](=[O:31])[CH2:29][N:28]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:6][N:7]=2)[C:27]1=[O:32]
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)nc3)CC2)nc1C
Reactant: CN1C(=O)CNC1=O
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CC(=O)N(C)C4=O)nc3)CC2)nc1C
Yield: 39.6 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (156 mg) described in Preparation Example 205 and 3-methylimidazolidine-2,4-dione (68 mg) described in Preparation Example 214 and by the reaction and treatment in the same manner as in Example 536, the title compound (67 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH:11]([N:12]([CH3:23])S(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:24][CH3:25])=[CH:7][CH:8]=2)[C:3]1=[CH:26][CH2:27][OH:28].[Na].[ClH:31]>N>[ClH:31].[CH3:1][C:2]1([CH3:29])[CH:11]([NH:12][CH3:23])[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:24][CH3:25])=[CH:7][CH:8]=2)[CH:3]1[CH2:26][CH2:27][OH:28]
Reactant: COc1ccc2c(c1)C(=CCO)C(C)(C)C(N(C)S(=O)(=O)c1ccc(C)cc1)C2
Agent: Cl
Agent: N
Agent: [Na]
Product: CNC1Cc2ccc(OC)cc2C(CCO)C1(C)C
Reaction time: 0.25 h

Procedure:
This compound, described already in Examples 12 and 13, can also be prepared as described in Example 13, however, starting from 2,2-dimethyl-1-(2-hydroxyethylidene)-7-methoxy-3-(N-methyl-p-toluenesulfonamido)-1,2,3,4-tetrahydronaphthalene. In this case, both the reduction of the olefinic double bond and the reductive cleavage of the p-toluenesulphonamido group are effectuated by the sodium metal dissolving in liquid ammonia. The endpoint of the reduction is reached if the blue colour persists for some 15 minutes. In this case again, a mixture of two stereoisomers is obtained, the total yield being 87% of crystalline hydrochloride.
Reaction SMILES: O.O.P([O-])(O)(O)=O.[Na+].[Cl:9][C:10]1[C:11]([C:20]2[C:21]([Cl:29])=[CH:22][C:23]([Cl:28])=[C:24]([CH:27]=2)[CH:25]=[O:26])=[N:12][N:13]([CH3:19])[C:14]=1[O:15][CH:16]([F:18])[F:17].OO.Cl([O-])=[O:33].[Na+].Cl>O.C(#N)C>[Cl:9][C:10]1[C:11]([C:20]2[C:21]([Cl:29])=[CH:22][C:23]([Cl:28])=[C:24]([CH:27]=2)[C:25]([OH:33])=[O:26])=[N:12][N:13]([CH3:19])[C:14]=1[O:15][CH:16]([F:17])[F:18]
Reactant: Cn1nc(-c2cc(C=O)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Reactant: [O-][Cl+][O-]
Agent: Cl
Agent: O=P([O-])(O)O
Agent: OO
Solvent: CC#N
Solvent: O
Product: Cn1nc(-c2cc(C(=O)O)c(Cl)cc2Cl)c(Cl)c1OC(F)F

Procedure:
A solution of 2.5 g (16 mmol) of sodium dihydrogen phosphate dihydrate in 25 ml of water was added dropwise at 10-15° C. to a solution of 21.3 g (60 mmol) of 5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-2,4-dichlorobenzaldehyde in 120 ml of acetonitrile. 6 ml of a 30% by weight hydrogen peroxide solution and then, in the course of two hours, a solution of 8.7 g (96 mmol) of sodium chlorite in 80 ml of water were added dropwise to this mixture. The reaction mixture was stirred for a further hour and then acidified with 3 N hydrochloric acid. The solids content was separated from the resulting suspension and dried. Yield: 13.7 g; m.p. 159-160° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:26]([N:28]4[CH2:33][CH2:32][CH:31]([N:34]5[C:39]6[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=6[CH2:37][O:36][C:35]5=[O:44])[CH2:30][CH2:29]4)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:17]([O:45][CH3:46])[CH:16]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.Cl>CCOC(C)=O>[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:26]([N:28]4[CH2:29][CH2:30][CH:31]([N:34]5[C:39]6[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=6[CH2:37][O:36][C:35]5=[O:44])[CH2:32][CH2:33]4)=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25]3)=[C:17]([O:45][CH3:46])[CH:16]=2)[CH2:10][CH2:9]1
Reactant: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C1(C(=O)N2CCC(N3C(=O)OCc4ccccc43)CC2)CCCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc(OC2CCNCC2)ccc1C1(C(=O)N2CCC(N3C(=O)OCc4ccccc43)CC2)CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a solution of 1-(1-(1-(4-(N-Boc-4-piperidinyloxy)-2-methoxyphenyl)cyclopentylcarbonyl)-piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one (0.15 g, 0.24 mmol) from Step 9 above in EtOAc (10 mL) at 0° C. was bubbled HCl gas for 10 min. The solution was warmed to ambient temperature and stirred for 1 h. The solvent was removed under reduced pressure to give the title compound as an amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:25]O)[S:5][C:6]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[O:9][N:8]=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:52]1[CH2:55][CH:54]([C:56]([O:58][CH3:59])=[O:57])[CH2:53]1.C(N(CC)C(C)C)(C)C>>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:25][N:52]2[CH2:55][CH:54]([C:56]([O:58][CH3:59])=[O:57])[CH2:53]2)[S:5][C:6]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:16][CH:17]=2)[O:9][N:8]=1
Reactant: Cc1cc(CO)sc1-c1noc(-c2ccc(Oc3ccccc3)cc2)n1
Reactant: COC(=O)C1CNC1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(Cc2cc(C)c(-c3noc(-c4ccc(Oc5ccccc5)cc4)n3)s2)C1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using {4-methyl-5-[5-(4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl}methanol (0.19 g, 0.51 mmol) that was obtained in Example 12 (12a), carbon tetrabromide (0.22 g, 0.66 mmol), triphenylphosphine (0.17 g, 0.66 mmol), methyl 3-azetidinecarboxylate hydrochloride (0.12 g, 0.77 mmol), and N,N-diisopropylethylamine (0.27 mL, 1.5 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (2:3) as the eluent to afford the title compound (0.20 g) in a yield of 85% as a pale yellowish oily product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8](=[O:10])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[C:3]([CH:8]([OH:10])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ncccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ncccc1Cl
Temperature: 25 °C
Yield: 79.3 %

Procedure:
To a stirred solution of 0.20 g (1.2 mmol) of 1-(3-chloropyridin-2-yl)ethanone in 5 mL of methanol was added 0.072 g (1.9 mmol) of sodium borohydride and the resulting solution was stirred with gradual warming to ambient temperature over 1 h. The reaction mixture was carefully quenched with water and then all volatiles were removed in vacuo. The remaining aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography eluting with a 0-100% ethyl acetate in hexanes gradient to afford the title compound as a colorless gum (0.15 g, 75% yield). LC-MS: m/z (ES) 158.2 (MH)+.
Reaction SMILES: C(OC(N([C@@H]1CCN(S([C:18]2[C:19]3[C:20](Br)=[CH:21][N:22]=[CH:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)(=O)=O)C1)C)=O)(C)(C)C.C(O[C:34]([N:36]([C@@H:38]1CCN[CH2:39]1)C)=O)(C)(C)C>>[CH2:23]([N:22]1[CH2:21][CH2:20][C@@H:38]([NH:36][CH3:34])[CH2:39]1)[C:24]1[CH:19]=[CH:18][CH:27]=[CH:26][CH:25]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCNC1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Product: CN[C@@H]1CCN(Cc2ccccc2)C1

Procedure:
(R)-3-[N-(tert-Butoxycarbonyl)-N-methylamino]-1-(4-bromo-5-isoquinolinesulfonyl)pyrrolidine (Intermediate 20b) can be prepared by using (R)-3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine obtained from (R)-1-benzyl-3-(methylamino)pyrrolidine (Tokyo Kasei Kogyo) instead of (S)-3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine according to the method described in a known literature (Barlocco et al., Tetrahedron, 1995, 51, 11547) in Example 1-3, Step A, and used in the method of Example 1-3, Step B in a similar manner to obtain the title compound as hydrochloride.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:9](Cl)=[O:10].[NH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14]1>>[C:20]1([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][CH:13]([NH:12][C:9]([C@@H:2]3[CH2:3][CH:4]4[CH2:7][CH2:8][N:1]3[CH2:6][CH2:5]4)=[O:10])[CH2:14]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Reactant: O=C(Cl)C1CC2CCN1CC2
Product: O=C(NC1CCN(CCc2ccccc2)C1)[C@@H]1CC2CCN1CC2

Procedure:
Quinuclidine-2-carbonyl chloride and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)quinuclidine-2-carboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]([Cl:15])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:37].Cl.Cl>C(OCC)(=O)C>[ClH:15].[ClH:37].[Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C(Cl)c2ccc(Br)cc2)c1
Reactant: CN1CCNCC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCOC(C)=O
Product: COc1cccc(C(c2ccc(Br)cc2)N2CCN(C)CC2)c1
Temperature: 25 °C

Procedure:
The crude benzhydryl chloride from above (6.5 g, 21 mmole) was added to 8.3 g (83 mmole) of 1-methylpiperazine and the reaction was heated to reflux for four hours. After cooling to room temperature, the mixture was dissolved in 100 ml of ethyl acetate and washed with two 150 ml portions of 1.0M sodium hydroxide, followed by two 150 ml portions of water and 100 ml of saturated aqueous sodium chloride. The solution was dried over magnesium sulfate and the solvent removed to give 6.5 g of crude product as an oil. The product was purified by chromatography on silica gel (Waters Prep 500) with dichloromethane:ethanol:triethylamine (100:0.2:0.1) to give a colorless oil. A portion was converted to the dihydrochloride salt with ethanolic hydrochloric acid and precipitated from ethanol with 1:1 hexane:diethyl ether to give 1-(α-(4-bromophenyl)-3-methoxybenzyl)-4-methylpiperazine dihydrochloride as a white powdery solid, mp. 195°-197° C. Calc. for C19H23BrN2O2HCl: C, 50.91; H, 5.62; N, 6.25; Total halogen calc. as Cl, 23.73. Found: C, 51.00; H, 5.66; N, 6.23; Total halogen calc. as Cl, 23.78.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29]([NH:1][N:2]2[N:11]=[C:10]([S:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:19])=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: Nn1nc(Sc2ccccc2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(Sc2ccccc2)c2ccccc2c1=O

Procedure:
The product from Example 57B and 2-(3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound: 1H NMR (500 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.35 (dd, J=7.9, 1.0, 1H), 8.09 (d, J=7.8, 1H), 8.04-7.98 (m, 1H), 7.94 (td, J=7.7, 1.1, 1H), 7.47-7.40 (m, 2H), 7.39-7.28 (m, 3H), 7.16 (tt, J=9.5, 2.3, 1H), 7.12-7.04 (m, 2H), 3.73 (s, 2H); MS (APCI+) M/Z 424 (M+H)+.
Reaction SMILES: [CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=3[CH:21]=4)[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2].[CH:30]1([CH2:36][CH2:37]C=O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([CH2:36][CH2:37][C:21]2[C:20]3[C:19]([F:22])=[CH:18][C:17]([F:23])=[CH:16][C:15]=3[N:14]=[C:13]3[C:24]4[N:10]([CH2:11][C:12]=23)[C:9](=[O:27])[C:8]2[CH2:7][O:6][C:5](=[O:28])[CH2:4][C@@:3]([CH2:1][CH3:2])([OH:29])[C:26]=2[CH:25]=4)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3c(F)cc(F)cc3nc2-1
Reactant: O=CCCC1CCCCC1
Product: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)cc(F)c1c2CCC1CCCCC1

Procedure:
The product of Example 100 is treated with 3-cyclohexylpropanal according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6](C)[C:5]=1[N:15](C(OC(C)(C)C)=O)[CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=O.CC(C)([O-])C.[K+].C(O)(=O)C.O>C1(C)C=CC=CC=1.ClCCl>[F:13][C:10]([F:11])([F:12])[C:8]1[CH:9]=[CH:4][C:5]2[NH:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[C:6]=2[CH:7]=1
Reactant: COC(=O)CCCN(C(=O)OC(C)(C)C)c1c(C)cc(C(F)(F)F)cc1C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCCNc2ccc(C(F)(F)F)cc21
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
Add a solution of methyl 2-[tert-Butoxycarbonyl-(3-methoxycarbonyl-propyl)-amino]-5-trifluoromethyl-benzoic acid methyl ester (0.5 g, 1.3 mmol) in toluene (25 mL) to a suspension of potassium tert-butoxide (0.3 g, 2.6 mmol) in toluene (75 mL) at 70° C., under an atmosphere of nitrogen, over a period of 30 min. After 2 h, cool the reaction to room temperature and quench the reaction with acetic acid (2.6 mmol). Dilute the reaction with water (100 mL) and dichloromethane (100 mL). Separate the organic phase, dry over sodium sulfate, and filter. Remove the solvent under vacuum then dissolve the crude intermediate in acetic acid (20 mL). Dilute with conc. HCl (20 mL) and water (10 mL) and heat the mixture to 100° C. for 4 h. After cooling to room temperature neutralize the reaction with 5N NaOH while cooling in an ice bath. Extract the organics with ethyl acetate (3×100 mL), dry over sodium sulfate, and filter. Remove the solvent under vacuum and chromatograph the product over silica gel using ethyl acetate/hexane (5-20%) to elute. This provides the title compound as an off white solid (0.13 g, 45%): H NMR (CDCl3, 400 MHz) δ 2.22-2.29 (m, 2H), 2.88 (t, J=6.4 Hz), 3.35 (t, J=6.8 Hz), 4.96 (bs, 1H), 6.84 (d, J=8.8 Hz, 1H), 7.46 (dd, J=2.0, 8.8 Hz, 1H), 8.02 (s, 1H).
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:7]([F:31])[CH:6]=[CH:5][C:4]=1[NH:32][S:33]([CH:36]1[CH2:38][CH2:37]1)(=[O:35])=[O:34]>>[N:24]1[C:16]([C:15]2[C:10]([NH:9][C:8]3[C:3]([F:2])=[C:4]([NH:32][S:33]([CH:36]4[CH2:37][CH2:38]4)(=[O:34])=[O:35])[CH:5]=[CH:6][C:7]=3[F:31])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:17]2[C:21]([NH:20][CH:19]=[N:18]2)=[N:22][CH:23]=1
Reactant: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)C1CC1
Agent: Cl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3[nH]cnc23)c1F)C1CC1
Reaction time: 2 h
Yield: 79 %

Procedure:
1M aqueous hydrochloric acid solution was added into the N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)9H-purin-6-yl)pyridin-2-ylamino)phenyl)cyclopropansulfonamide (20 mg, 0.038 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 13 mg of the target compound, N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)cyclopropansulfonamide (percentage yield: 79%), was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([F:11])=[CH:13][CH:14]=2)=[O:7])=[CH:4][N:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)cc1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.2 %

Procedure:
To a suspension of 6-chloronicotinoyl chloride (10.5 g, 59.7 mmole) in dry dichloromethane (100 mL) was added 4-fluoroaniline (5.6 mL, 59.7 mmole), followed by the dropwise addition of N,N-diisopropylethylamine (21 mL, 119 mmol). After stirring for 90 min at room temperature, the mixture was diluted with ethyl acetate (20 mL) and washed with water. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by recrystallization using ethyl acetate/hexanes gave 13.8 g (92%) of a white solid. 1H NMR (300 MHz, CDCl3) δ7.09–7.12 (m, 2H), 7.47–7.50 (m, 1H), 7.56–60 (m, 2 H), 7.7 (bs, 1H), 8.15–8.18 (m, 1H), 8.84 (m, 1H); MS (EI) m/z 251.13 (M+H)+.