Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]([CH3:22])[CH:13]=2)[N:3]=1.[I:23][C:24]1[N:25]=[CH:26][NH:27][CH:28]=1>>[I:23][C:24]1[N:25]=[CH:26][N:27]([C:2]2[N:3]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]([CH3:22])[CH:13]=3)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=2)[CH:28]=1
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1C(F)(F)F
Reactant: Ic1c[nH]cn1
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-chloro-6-(3-methyl-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidine (example A.38) (2.04 g, 6.0 mmol) and commercially available 4-iodo-imidazole (1.28 g, 6.6 mmol) according to the general procedure IVa. Obtained as an off-white solid (2.83 g, 95%). MS (ISP) 499.3 [(M+H)+]; mp 190° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([C:16]([F:19])([F:18])[F:17])=[C:11]([C:13]([OH:15])=O)[N:12]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:31][CH2:30][C@H:29]([OH:32])[CH2:28]2)=[N:25][CH:26]=1>>[OH:32][C@H:29]1[CH2:30][CH2:31][N:27]([C:24]2[N:25]=[CH:26][C:21]([NH:20][C:13]([C:11]3[N:12]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Br:1])[O:9][C:10]=3[C:16]([F:19])([F:18])[F:17])=[O:15])=[CH:22][CH:23]=2)[CH2:28]1
Reactant: Nc1ccc(N2CC[C@H](O)C2)nc1
Reactant: O=C(O)c1nc(-c2ccccc2Br)oc1C(F)(F)F
Product: O=C(Nc1ccc(N2CC[C@H](O)C2)nc1)c1nc(-c2ccccc2Br)oc1C(F)(F)F

Procedure:
With a method similar to example 43 above, 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-amide was prepared from 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and (S)-1-(5-Amino-pyridin-2-yl)-pyrrolidin-3-ol. LCMS calcd for C20H16BrF3N4O3 m/e 497, obsd 498.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[O:6][CH2:7][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:9]=1.CN(C)C1C=CC=CC=1.Cl[C:30]([N:32]=[C:33]=[O:34])=[O:31]>ClCCl>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]1[C:33](=[O:34])[NH:32][C:30](=[O:31])[N:9]2[CH:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:7][O:6][C:5]=12
Reactant: O=C=NC(=O)Cl
Reactant: Fc1ccccc1CC1=NC(c2ccccc2)CO1
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: O=c1[nH]c(=O)n2c(c1-c1ccccc1F)OCC2c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.4 %

Procedure:
To 2-(2-fluorobenzyl)-4-phenyloxazoline (0.250 g, 0.980 mmol) and N,N-dimethylaniline (0.134 g, 1.09 mmol) in dichloromethane (1.5 mL) at 0° C. was added dropwise chlorocarbonyl isocyanate (0.103 g, 0.980 mmol). The mixture was allowed to warm to room temperature and was stirred for 24 h. The solution was concentrated, dissolved in ethyl acetate (1 mL) and filtered through a short pad of silica gel, eluating with ethyl acetate (150 mL). Concentration gave green-yellow crystals (0.300 g) which were used immediately in the next step due. MS=325.1 ((M+H)+).
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH3:5])C.[NH:16]([C:18]1[N:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)[NH2:17].O>ClCCl.CO>[F:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[N:16]([C:18]3[N:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[N:17]=[C:4]([CH3:5])[N:6]=2)=[CH:13][CH:12]=1
Reactant: NNc1ccc(S(N)(=O)=O)cn1
Reactant: CCOC(C)=NC(=O)c1ccc(F)cc1
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(-c2ccc(F)cc2)n(-c2ccc(S(N)(=O)=O)cn2)n1
Reaction time: 8 h
Yield: 56.1 %

Procedure:
N-(1-ethoxy-ethylidene)-4-fluoro-benzamide 438 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and 6-hydrazinopyridine-3-sulfonic acid amide 433 mg (2.23 mmol) was added to the solution and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 6-[5-(4-fluoro-phenyl)-3-methyl-[1,2,4]triazole-1-yl]-pyridine-3-sulfonic acid amide (391 mg, yield: 56%) was obtained as a solid phase.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][C:8]=2[C@@H:19]([O:24][C:25]2[N:30]=[C:29]([NH2:31])[N:28]=[C:27]([N:32]3[CH2:53][CH2:52][C:35]4([CH2:39][N:38](C(OC(C)(C)C)=O)[C@H:37]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:36]4)[CH2:34][CH2:33]3)[CH:26]=2)[C:20]([F:23])([F:22])[F:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][C:8]=2[C@@H:19]([O:24][C:25]2[N:30]=[C:29]([NH2:31])[N:28]=[C:27]([N:32]3[CH2:53][CH2:52][C:35]4([CH2:39][NH:38][C@H:37]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:36]4)[CH2:34][CH2:33]3)[CH:26]=2)[C:20]([F:22])([F:23])[F:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4cc(-c5ccccc5)ccc4-c4ccccc4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4cc(-c5ccccc5)ccc4-c4ccccc4)C(F)(F)F)nc(N)n3)CC2)CN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-tert-butyl 3-ethyl 8-(6-((R)-1-([1,1′:4′,1″-terphenyl]-2′-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (550 mg, 0.75 mmol) in CH2Cl2 (4 mL) was added TFA (2.0 mL) dropwise at 0° C. The reaction mixture was stirred at RT for 2 h, and concentrated in vacuo. The pH was adjusted to 7-8 with a saturated aqueous NaHCO3 solution. The aqueous layer was extracted with CH2Cl2. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (CH2Cl2/MeOH) provided (S)-ethyl 8-(6-((R)-1-([1,1′:4′,1″-terphenyl]-2′-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a white solid.
Reaction SMILES: [C:1]1([C:15](OC)=[O:16])[CH:6]=[C:5]([C:7](OC)=[O:8])[CH:4]=[C:3]([C:11](OC)=[O:12])[CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:8][CH2:7][C:5]1[CH:4]=[C:3]([CH2:11][OH:12])[CH:2]=[C:1]([CH2:15][OH:16])[CH:6]=1
Reactant: COC(=O)c1cc(C(=O)OC)cc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc(CO)cc(CO)c1
Temperature: 25 °C
Yield: 50.6 %

Procedure:
A solution of trimethyl 1,3,5-benzenetricarboxylate (8.83 g, 0.035 M; Aldrich) in THF (125 mL) is added dropwise over a period of 45 minutes to a stirred mixture of lithium aluminum hydride (3.98 g, 0.105 M) and dry THF (150 mL) under a nitrogen atmosphere. The initial phase of the addition results in vigorous reaction and consequently the addition is very slow at first. As the ester solution is added, an orange mass forms when the drops came in contact with the LiAlH4 mixture. A yellowish-green mixture results and is stirred at room temperature. The excess LiAlH4 is quenched carefully by the addition of ethyl acetate and the resulting mixture is acidified with aqueous 2N HCl solution until the pH is <3 and aluminum salts have dissolved. The layers are separated and the aqueous layer is extracted 3 times with additional ethyl acetate and then with methylene chloride. The organic extract layers are dried (sodium sulfate), filtered, and concentrated under reduced pressure to give a white solid (2.98 g, 51%). Recrystallization from acetonitrile-methylene chloride gives the title compound as white crystals (1.13 g) which appear to be hygroscopic when collected by suction filtration. The crystals are dried several days over P2O5 in a vacuum desiccator after which they have amp of 76.5°-78° C.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.Cl[Si](CC)(CC)CC.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:29]2[CH:30]=[CH:31][C:32]3[C:33]([CH:44]=2)=[C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[O:35][N:36]=3)=[O:28])=[CH:23][CH:22]=1>C1COCC1>[Cl:43][C:39]1[CH:38]=[C:37]([C:34]2[O:35][N:36]=[C:32]3[CH:31]=[CH:30][C:29]([C:27]([C:24]4[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=4)([C:11]4[N:7]([CH3:6])[CH:8]=[N:9][CH:10]=4)[OH:28])=[CH:44][C:33]=23)[CH:42]=[CH:41][CH:40]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2noc(-c3cccc(Cl)c3)c2c1
Reactant: Cn1ccnc1
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2noc(-c3cccc(Cl)c3)c2c1
Temperature: -70 °C
Reaction time: 0.75 h
Yield: 25 %

Procedure:
Butyllithium in hexanes (10 ml) was added slowly at −70° C. under N2 flow to a solution of 1-methylimidazole (1.31 g) in THF (30 ml). The mixture was stirred at −70° C. for 45 minutes. Chlorotriethylsilane (2.7 ml) was added. The mixture was allowed to warm to 15° C. and cooled to −70° C. Butyllithium (10 ml) was added slowly. The mixture was stirred at −70° C. for 1 hour, allowed to warm to −15° C. and cooled to −70° C. A solution of intermediate (6-b) (4.9 g) in THF (60 ml) was added. The mixture was stirred at −70° C. for 30 minutes, then hydrolyzed with water, extracted with ethyl acetate and decanted. The organic layer was dried, filtered and the solvent was evaporated. The residue (8.2 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0.2) and crystallized from 2-propanone/diethyl ether. The precipitate was filtered off and dried, yielding 1.5 g (25%) of (±)-3-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-2,1-benzisoxazole-5-methanol (interm. 6-c).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].[CH2:33]([O:35][CH2:36][CH2:37][N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[NH:47][CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[CH3:34]>>[CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:51]2[CH2:50][CH2:49][CH:48]([NH:47][C:39]3[N:38]([CH2:37][CH2:36][O:35][CH2:33][CH3:34])[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N:40]=3)[CH2:53][CH2:52]2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8]1)=[O:6]
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: COc1cc(OC)c(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc1OC
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)cc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(2,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl) pyrrolidine and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.Cl[Sn]Cl.[OH-].[Na+]>Cl>[NH2:1][C:4]1[CH:11]=[C:10]([C:12]2[C:17]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(-c2ncccc2C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: N#Cc1ccc(-c2ncccc2C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-water cooled solution of 2-nitro-4-(3-trifluoromethyl-pyridin-2-yl)-benzonitrile (0.44 mmol) in conc. HCl (6 mL) add SnCl2 (1.457 mmol). Stir the mixture 2 h at room temperature. neutralize with NaOH, extract with EtOAc, dry over Na2SO4, and concentrate under vacuum. Purify the residue by flash chromatography (4:1 hexanes/EtOAc) to give 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzo-nitrile.
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[C:14]([C:26]([NH2:28])=[O:27])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:40][CH2:41][CH2:42][N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[C:34]([NH:36][C:37](=[O:39])[CH3:38])[CH:35]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CN1C(=O)CCC1>[C:37]([NH:36][C:34]1[CH:35]=[C:30]([NH:29][C:11]2[N:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[C:14]([C:26]([NH2:28])=[O:27])=[CH:13][N:12]=2)[CH:31]=[CH:32][C:33]=1[O:40][CH2:41][CH2:42][N:43]1[CH2:44][CH2:45][CH2:46][CH2:47]1)(=[O:39])[CH3:38]
Reactant: CC(=O)Nc1cc(N)ccc1OCCN1CCCC1
Reactant: NC(=O)c1cnc(On2nnc3ccccc32)nc1NCc1cccc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1cc(Nc2ncc(C(N)=O)c(NCc3cccc(F)c3)n2)ccc1OCCN1CCCC1
Temperature: 100 °C
Yield: 60.4 %

Procedure:
To a solution of 2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-(3-fluorobenzylamino)pyrimidine-5-carboxamide (57 mg, 0.15 mmol) in NMP (0.6 mL) was added N-(5-amino-2-(2-(pyrrolidin-1-yl)ethoxy)phenyl)acetamide (47 mg, 0.18 mmol) and pTsOH.H2O (28 mg, 0.15 mmol). The mixture was heated at 100° C. for 2 h, cooled to room temperature, and purified by preparative HPLC to give 2-(3-acetamido-4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)-4-(3-fluorobenzylamino)pyrimidine-5-carboxamide (46 mg). MS found for C26H30FN7O3 as (M+H)+ 508.5. λ 248.5.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][NH:7][C:8](=[O:40])[C@@H:9]([CH3:39])[NH:10][C:11](=[O:38])[C@H:12]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:37])=[CH:24][CH:23]=1)[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].Cl>CC(C)=O>[C:17]([O:16][C:14]([NH:13][C@H:12]([C:11]([NH:10][C@@H:9]([C:8]([NH:7][CH2:6][C:5]([OH:41])=[O:4])=[O:40])[CH3:39])=[O:38])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]2[C:31]([Cl:37])=[CH:32][CH:33]=[CH:34][C:35]=2[Cl:36])=[CH:26][CH:27]=1)=[O:15])([CH3:18])([CH3:19])[CH3:20]
Reactant: COC(=O)CNC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O

Procedure:
Aqueous 1N sodium hydroxide (12 ml.) is added to a suspension of t-butoxycarbonyl-O-(2,6-dichlorobenzyl)-L-tyrosyl-D-alanylglycine methyl ester (Step 2, 4.7 g.) in acetone (25 ml.) stirred with a magnetic stirrer. After 41/2 hours the solution is acidified to pH 2 with 4N hydrochloric acid. After an hour a white precipitate is removed by filtration and dried under vacuum to give t-butoxycarbonyl-O-(2,6-dichlorobenzyl)-L-tyrosyl-D-alanylglycine.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][CH2:7][CH2:8][CH2:9][CH:4]2[CH2:3][CH:2]1O.[N+](C1C=C([N+]([O-])=O)C=CC=1C([O-])=O)([O-])=[O:12]>CCCCCC.C(O)(C)C>[O:1]1[C@@H:5]2[CH2:6][CH2:7][CH2:8][C@H:9]([OH:12])[C@@H:4]2[CH2:3][CH2:2]1
Reactant: OC1CC2CCCC=C2O1
Reactant: O=C([O-])c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CCCCCC
Solvent: CC(C)O
Product: O[C@H]1CCC[C@H]2OCC[C@@H]12

Procedure:
Racemic alcohol 12 (70 mg, 0.5 mmol) was dissolved in THF (5 mL), vinyl acetate (120 μL, 1.25 mmol) was added. Amano lipase PS-30 (30 mg) was added and the resulting suspension was stirred at 15-17° C. After 48 h, 30 mg additional enzyme was added and the mixture was left for additional 48 h until which ca. 54% conv. was reached (NMR and GC). The resulting suspension was diluted with Et2O and filtered on celite, the filter cake rinsed with Et2O. After evaporation of the remaining solvent, the residue was purified by column chromatography using hexanes/EtOAc (5:1, 3:1 then 2:1) as the eluent to yield acetyl furanol 13 (38 mg, 41%) and the desired enantioenriched (−)-hexahydrobenzofuranol (−)-12 (24 mg, 35%). The enantiomeric excess of the 2,4-dinitrobenzoate derivative of (−)-12 was determined to be 98.8% ee by chiral HPLC, Column ChiralPak IA, hexane/isopropanol (90/10 to 50/50, 40 min), 1 mL/min, 35° C., λ=254 nm, Rt Major=16.54 min, Rt minor=37.1 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([OH:12])=O)[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.ClC(OCC)=O.[C:26]1([CH:32]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:33]2[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH2:35][CH2:34]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][N:36]2[CH2:37][CH2:38][N:33]([CH:32]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:34][CH2:35]2)=[O:12])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)C=Cc1cncc(F)c1
Reactant: NCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(C=Cc1cncc(F)c1)NCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 2 h
Yield: 36.6 %

Procedure:
To a stirred suspension of 0.29 g of 3-(5-fluoro-3-pyridyl)acrylic acid in 15 ml of dry tetrahydrofuran, 0.24 g of triethylamine is added at room temperature. The resulting solution is cooled to between -10° C. and -5° C., and a solution of 0.25 g of ethyl chloroformate in 2 ml of tetrahydrofuran is added slowly. After the mixture is stirred at the same temperature for 2 hours, a solution of 0.75 g of 4-(4-diphenylmethyl-1-piperazinyl)butylamine in 2 ml of dry tetrahydrofuran is added. The mixture is stirred for 1 hour at between -10° C. and -5° C. and then at room temperature overnight. The insoluble materials are filtered off, and the filtrate is concentrated. The residue is chromatographed on silica gel with chloroform-methanol (40:1) to give 0.3 g of the title compound. m.p. 128°-129° C. (recrystallized from toluene-hexane)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH2:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([CH3:35])[N:34]=1)[C:30]#[N:31]>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH:19][C:27]3[CH:28]=[C:29]([CH:32]=[C:33]([CH3:35])[N:34]=3)[C:30]#[N:31])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1cc(C#N)cc(Cl)n1
Reactant: NCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C#N)cc(NCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)n1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
2-{(1S,2S)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanamine from step 3 of Example 5 (59 mg, 0.21 mmol) was dissolved in DMSO (1.0 ml). K2CO3 (86 mg, 0.62 mmol) and 2-chloro-6-methylisonicotinonitrile (31 mg, 0.21 mmol) from step 2 of this example were added and the mixture stirred at 150° C. overnight. The mixture was cooled to RT, diluted with water (30 ml), and extracted with EtOAc (3×30 ml). The organic fractions were combined, washed with brine, dried over Na2SO4, filtered and the volatiles removed in vacuum. The product was purified by chromatography on SiO2 eluting with 20% EtOAc:Hexanes to give the titled compound. LRMS calc: 396.18; obs: 397.27 (M+1).
Reaction SMILES: [C:1]([CH:3]=[CH:4][NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])C(OCC)=O)#[N:2].C(O)(=O)C>C(O)C.C([O-])C.[Na+]>[NH2:2][C:1]1[CH:3]=[CH:4][NH:5][C:6]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(NC=CC#N)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1[nH]ccc1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 54.4 %

Procedure:
Into a 1000-mL round-bottom flask was placed a solution of diethyl 2-(2-cyanovinylamino)malonate (30 g, 119.3 mmol, 1.00 equiv, 90%) in ethanol (420 mL) and sodium ethanolate (80 mL, 21%). The resulting solution was stirred for 3 days at room temperature. After the addition of acetic acid (15 ml), the resulting mixture was concentrated under vacuum, dissolved in 200 mL of dichloromethane, washed with 2×100 mL of saturated aqueous sodium bicarbonate and 1×100 mL of brine, dried over anhydrous sodium sulfate and concentrated. The residue was dried in HV to afford 10 g (49%) of ethyl 3-amino-1H-pyrrole-2-carboxylate as an orange syrup.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:21]C)[CH:16]=3)[S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.I>>[CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:21])[CH:16]=3)[S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc2sc3cccc(NCCN(C)C)c3c(=O)c2c1
Agent: I
Product: CN(C)CCNc1cccc2sc3ccc(O)cc3c(=O)c12

Procedure:
mixing the product of step (c) with HI under conditions to form 1-(2-dimethylaminoethylamino)-7-hydroxythioxanthenone;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([C:27](O)=[O:28])[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([C:27]([N:52]5[CH2:57][CH2:56][O:55][CH2:54][CH2:53]5)=[O:28])[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C1COCCN1
Reactant: O=C(O)[C@H]1CC[C@H](Nc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Product: O=C([C@H]1CC[C@H](Nc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1)N1CCOCC1

Procedure:
Prepared from 4-[(3-chloro-4-fluorophenyl)amino]-6-[trans-4-carboxycyclohexylamino]pyrimido[5,4-d]pyrimidine by reaction with O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, triethylamine and morpholine. Melting point: 221°-225° C.; Rf : 0.47 (silica gel; petroleum ether/ethyl acetate/methanol=10:8:3)
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:18]=3[C:19]#[N:20])[CH2:12][CH2:11]2)[CH2:4][CH2:3]1.F[C:27](F)(F)[C:28](O)=[O:29].C(Cl)(=O)C>>[C:19]([C:18]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:17]=1[O:16][CH:13]1[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([NH:1][C:28](=[O:29])[CH3:27])[CH2:3][CH2:4]2)[CH2:15][CH2:14]1)#[N:20]
Reactant: O=C(O)C(F)(F)F
Reactant: N#Cc1cc(F)ccc1OC1CCN(CC[C@H]2CC[C@H](N)CC2)CC1
Solvent: CC(=O)Cl
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCC(Oc3ccc(F)cc3C#N)CC2)CC1

Procedure:
According to the synthesis of N-Trans(4-{2-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamide (example 8), the title compound was prepared from Trans 2-{1-[2-(4-Amino-cyclohexyl)-ethyl]-piperidin-4-yloxy}-5-fluoro-benzonitrile; trifluoroacetic acid salt and acetylchloride MS (m/e): 381.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:4][CH:3]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.[Cu](I)I>[F:27][C:22]1[CH:21]=[C:20]([N:4]2[C:5]3[C:10](=[C:9]([O:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:8]=[CH:7][CH:6]=3)[C:2]([CH3:1])=[CH:3]2)[CH:25]=[CH:24][C:23]=1[OH:26]
Reactant: Cc1c[nH]c2cccc(OCc3ccccc3)c12
Reactant: Oc1ccc(Br)cc1F
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cn(-c2ccc(O)c(F)c2)c2cccc(OCc3ccccc3)c12
Temperature: 190 °C

Procedure:
To a solution of 3-methyl-4-[(phenylmethyl)oxy]-1H-indole (R. A. Heacock et al. Canadian Journal of Chemistry, (1964), 42(3), 514) (617 mg, 2.60 mmol) in N-methyl-2-pyrrolidinone (10 mL) was added 4-bromo-2-fluorophenol (0.28 mL, 2.60 mmol), copper iodide (96 mg, 0.50 mmol) and potassium carbonate (867 mg, 6.28 mmol). The reaction mixture was heated in a Biotage Initiator™ Microwave Synthesizer at 190° C. for 3 hours. The mixture was filtered through a pad of Celite which was subsequently washed with ethyl acetate. The ethyl acetate solution was washed with water and then the aqueous layer re-extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and then concentrated in vacuo. The product was purified by silica gel chromatography eluting with 0-30% ethyl acetate in hexane to yield the title compound (D2) (147 mg).