Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([C:14](=O)[NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:14][NH2:15])([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(C(N)=O)CCN(C(=O)OC(C)(C)C)CC1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(CN)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 5.7 %

Procedure:
A 1M solution of borane complex in THF (2.25 mL, 2.25 mmol) was added to a cooled solution (0° C.) of 4-tert-butoxycarbonylamino-4-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (107 mg, 0.3 mmol) in THF (4.3 mL). After stirring for 5 minutes at 0° C. the reaction mixture was allowed to warm to room temperature. The reaction mixture was further warmed to 60° C. and stirred overnight. The reaction mixture was cooled to room temperature and methanol (5.1 mL) was added. After stirring for 30 minutes, the solvents were removed by evaporation. The reaction mixture was partitioned between an aqueous saturated solution of ammonium chloride (10 mL) and dichloromethane (10 mL). After further extraction of the aqueous phase with dichloromethane (20 mL), the combined organic phases were dried (Mg2SO4), filtered and concentrated. Flash column chromatography on silica, eluting with 5% methanol in dichloromethane, gave 4-aminomethyl-4-tert-butoxycarbonylamino-piperidine-1-carboxylic acid tert-butyl ester (5.5 mg, 0.017 mmol, 6%). LC-MS (LCT2) m/z 352 [M+Na+], Rt 7.16 min.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[C:21]1([OH:31])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.[OH-].[Na+]>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:31][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: Oc1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2cccc3ccccc23)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with Naphthalen-1-ol under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C23H24O5 [M+Na]+: 403, [M+H]+: 381.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:30]3[CH:35]=[CH:34][N:33]=[C:32](SC)[N:31]=3)[C:10]3[C:11]([N:29]=2)=[N:12][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:14][CH:15]=3)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[C:49]1([C@@H:55]([NH2:57])[CH3:56])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C(Cl)Cl.CC(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([NH:57][C@H:55]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[CH3:56])[N:31]=3)[C:10]3[C:11]([N:29]=2)=[N:12][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:14][CH:15]=3)=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CSc1nccc(-n2c(-c3ccc(F)cc3)nc3nc(N4CCN(C(=O)OC(C)(C)C)CC4)ccc32)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@H](Nc1nccc(-n2c(-c3ccc(F)cc3)nc3nc(N4CCN(C(=O)OC(C)(C)C)CC4)ccc32)n1)c1ccccc1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
2-(4-Fluorophenyl)-1-(2-methylthio-4-pyrimidinyl)-5-(4-tert.butoxycarbonyl-1-piperazinyl)imidazo[4,5-b]pyridine (106 mg, 0.2 mmol) is dissolved in CH2Cl2/HOAc 1:1 (10 ml), combined with mCPBA (113 mg 70%, 0.24 mmol) and stirred for 15 min. The reaction mixture is poured on water and extracted with CH2Cl2 three times. The combined organic phases are dried over Na2SO4. filtered and evaporated to dryness to yield the crude sulfoxide (100 mg), which is dissolved in 1-(S)-phenylethylamine (0.2 ml) and heated to 120° C. for 1 h. Purification over SiO2 (acetone/hexanes 1:1) yielded the title compound as colorless foam (45 mg 35%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1.[CH3:9][N:10]=[C:11]=[S:12]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:11]([NH:10][CH3:9])=[S:12])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: CN=C=S
Solvent: CC#N
Product: CNC(=S)Nc1ccc(Cl)nc1
Yield: 70.6 %

Procedure:
A mixture of 4.07g of 2-chloro-5-aminopyridine, 2.55g of methyl isothiocyanate and 30ml of acetonitrile was refluxed for 13.5 hours, to which 0.70g of additional methyl isothiocyanate was added and the mixture was refluxed for 3.5 hours. The reaction mixture was concentrated, and the residue was purified by a column chromatography [developing solvent: dichloromethaneethyl acetate (1: 1)] to afford 4.51g of 1-(6-chloro-3-pyridyl)-3-methylthiourea.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16]C(=O)CC)[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.[CH2:38]([O:45][CH2:46][C:47](Cl)=[O:48])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:38]([O:45][CH2:46][C:47]([NH:16][C@H:14]1[CH2:15][C@@H:11]([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([Cl:1])=[N:3][C:4]=3[NH:23][CH2:24][CH:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:12]([OH:22])[C@@H:13]1[OH:21])=[O:48])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(Cl)COCc1ccccc1
Product: O=C(COCc1ccccc1)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Intermediate J) by replacing propionyl chloride with benzyloxy-acetyl chloride.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:22]([CH2:34][CH:35]=O)[CH2:23][N:24]([CH3:33])[C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:18]=[CH:19][C:20]=1[Cl:21].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([CH:22]([CH2:34][CH2:35][N:5]2[CH2:6][CH2:7][C:2]([OH:1])([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:3][CH2:4]2)[CH2:23][N:24]([CH3:33])[C:25](=[O:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CN(CC(CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(CC(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.4 %

Procedure:
A solution of 4-hydroxy-4-phenyl-piperidine (1.99 g) in methanol (20 mL) was cooled to 0° C. and the pH was adjusted to 8 by adding acetic acid. To this solution was added N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide (3.57 g) in methanol (20 mL), and the resulting reaction mixture was treated with sodium cyanoborohydride (0.765 g). Upon warming to the room temperature, the reaction mixture was stirred for 16 hours and treated with saturated sodium bicarbonate solution. The solution was extracted with dichloromethane, dried (anhydrous sodium sulfate) and evaporated. The resulting material was purified by chromatography, with dichloromethane:methanol (90:10) as the eluent, to give the piperidine (2.42 g); NMR (CDCl3): 1.5-2.5 (m, 10), 2.68 (broad, 4), 3.47 (s, 3), 3.5-3.57 (m, 1), 6.8-7.5 (m, 13); MS: m/z=511(M+1). This material was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)[CH3:11]>CC(N(C)C)=O>[CH2:10]([O:12][C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:16][N:17]1[CH2:18][CH2:19][CH:20]([NH:23][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=2)[CH2:21][CH2:22]1)[CH3:11]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CC(=O)N(C)C
Product: CCOc1cc(CN2CCC(Nc3ccc(C#N)cn3)CC2)ccc1OC
Yield: 4 %

Procedure:
A solution of 6-chloro-nicotinonitrile (20.8 mg, 0.15 mmol, 1.0 equiv; commercially available) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol, 1.2 equiv; intermediate A1) in DMAc (1.5 mL) was heated by microwave irradiation to 180° C. for 10 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 2.2 mg (4%) of the title compound. MS (ISP): 367.3 [M+H]+.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6]C=[CH:4][CH:3]=1.CI.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.[CH3:22][N:23]([CH3:26])[CH:24]=O>>[CH3:22][N:23]([CH3:26])[C:24]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN(C)c1ccccc1
Reaction time: 8 h

Procedure:
The aniline derivative (1.4 g, 7.3 mmol) obtained in Step 1 was dissolved in dimethylformamide (50 ml), methyl iodide (1.4 ml, 22 mmol) and potassium carbonate (3.0 g, 22 mmol) were added, and the mixture was stirred overnight. A treatment according to a conventional method using ethyl acetate as an extraction solvent gave a crude product, which was successively purified by silica gel column chromatography to give a dimethylaniline derivative (1.1 g, 5.0 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([O:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[Cl:26])[CH:12]=[CH:11][C:10]=1Br)[CH2:6][CH3:7])[CH3:2].[CH3:29][N:30](C)C=O>>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([O:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[Cl:26])[CH:12]=[CH:11][C:10]=1[C:29]#[N:30])[CH2:6][CH3:7])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(CC)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Br
Product: CCOC(=O)C(CC)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1C#N
Reaction time: 4 h

Procedure:
A 10 g of ethyl-α-[2-bromo-5-(2-chloro-4-trifluoromethyl phenoxy) phenoxy]butyrate was dissolved in 20 ml of dimethylformamide. A 2.5 g of cuprous cyanide was added to the solution and the reaction was conducted at 145° to 150° C for 4 hours with stirring the mixture. The reaction mixture was poured into suitable amount of an aqueous solution of ferric chloride. The product was extracted with chloroform. The extract was washed with water and was dried. The chloroform was evaporated off and the product was distilled at reduced pressure to obtain 6 g of the object compound having a boiling point of 200° to 205° C/1 mmHg.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH:6]([C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)[CH2:7][C:8](=[O:21])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:18]=[C:17]([NH2:19])[N:16]=[C:15]([NH2:20])[CH:14]=1)C.[Li+].[OH-]>C1COCC1.O>[NH2:19][C:17]1[N:16]=[C:15]([NH2:20])[CH:14]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][C:8](=[O:21])[CH2:7][CH:6]([C:22]2[CH:27]=[N:26][C:25]([CH3:28])=[N:24][CH:23]=2)[CH2:5][C:4]([OH:29])=[O:3])[N:18]=1
Reactant: CCOC(=O)CC(CC(=O)CCCCc1cc(N)nc(N)n1)c1cnc(C)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncc(C(CC(=O)O)CC(=O)CCCCc2cc(N)nc(N)n2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The ester 15-6 (20 mg, 0.05 mmol) in THF (10 mL) and water (10 mL) was treated with 1 N LiOH (1.0 mL, 1.0 mmol). After stirring at room temperature for 1 hour, the solution was concentrated to 5 mL and purified by reverse phase HPLC (preppak C-18 column; water/acetonitrile/0.1% TFA gradient). After lyophilization, the title compound 15-7 (TFA salt) was obtained as a white powder.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH2:8][CH2:9][CH3:10])[CH2:5][CH2:6][CH3:7].[C:11]1([S:17]([O-:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+]>>[CH2:5]([C:4]([CH2:8][CH2:9][CH3:10])=[CH:3][CH2:2][S:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:19])=[O:18])[CH2:6][CH3:7]
Reactant: O=S([O-])c1ccccc1
Reactant: CCCC(=CCBr)CCC
Agent: [Na+]
Product: CCCC(=CCS(=O)(=O)c1ccccc1)CCC

Procedure:
Using the procedure of Example I, 1-bromo-3-propyl-2-hexene was reacted with sodium phenyl sulfinate to form (3-propyl-2-hexenyl)-phenyl sulfone which was then reacted with ethyl β,β-dimethyl-acrylate to form ethyl dl-trans 3,3-dimethyl-2-(2'-propyl-1'-pentenyl)-cyclopropanecarboxylate having a boiling point of 80° C. at 0.06 mm Hg and a refractive index nD22 =1.464. The said ethyl ester was hydrolyzed under alkaline conditions to form dl-trans 3,3-dimethyl-2-(2'-propyl-1'-pentenyl)-cyclopropane carboxylic acid having a boiling point of 116° C. at 0.05 mm Hg and a refractive index nD22 =1.4755 which was then reacted with thionyl chloride to obtain dl-trans 3,3-dimethyl-2-(2'-propyl-1'-pentenyl)-cyclopropanecarboxylic acid chloride having a boiling point of 75° C. at 0.04 mm Hg and a refractive index nD24 =1.4795.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].[CH2:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C:11]1=O.C([BH3-])#N.[Na+]>C(O)C.CO>[OH:8][CH2:7][C@H:5]([NH:6][CH:11]1[CH2:10][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)[C:4]([O:3][CH3:2])=[O:9]
Reactant: O=C1Cc2ccccc2C1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: COC(=O)[C@H](CO)NC1Cc2ccccc2C1
Reaction time: 0.5 h

Procedure:
L-serine methyl ester hydrochloride (0.05 moles, 7.78 g) is dissolved in absolute ethanol (400 ml) and methanol (40 ml), added with 2-indanone (0.05 moles, 6.74 g) and sodium cyanoborohydride (0.55 moles, 3.64 g) under stirring in 30 minutes. The mixture is stirred at r.t. for 5 hours, then evaporated to dryness under vacuum and the residue is taken up into water (150 ml) and ethyl acetate (150 ml). The phases are separated and the aqueous phase is further extracted with ethyl acetate (200 ml). The combined organic phases are extracted with a 0.2 N HCl solution (2×200 ml). The aqueous solution is separated, adjusted to pH=8 with sodium bicarbonate and extracted with ethyl acetate (2×300 ml). The organic solution is separated, dried over sodium sulfate and evaporated under vacuum. The resulting product is dried under vacuum at r.t. Yield: 8.4 g (71.4%)
Reaction SMILES: [NH2:1][OH:2].[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8].C(=O)([O-])[O-].[K+].[K+]>CCO>[Br:3][C:4]1[CH:5]=[C:6]([C:7](=[N:1][OH:2])[NH2:8])[CH:9]=[CH:10][CH:11]=1
Reactant: NO
Reactant: N#Cc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NC(=NO)c1cccc(Br)c1
Temperature: 120 °C

Procedure:
Hydroxylamine (1.00 mL of a 50% aqueous solution, 16.3 mmol) was added to a solution of 3-bromobenzonitrile (750 mg, 4.12 mmol) and potassium carbonate (1.00 mg, 7.24 μmol) in EtOH (3.00 mL). The resulting mixture was heated to 120° C. in a sealed microwave vial for 40 min. After cooling to rt, the reaction mixture was concentrated in vacuo to afford the title compound i-3a. m/z (ES) 215 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].Cl[C:24]1[N:29]=[CH:28][N:27]=[C:26]2[NH:30][N:31]=[CH:32][C:25]=12.C(N(C(C)C)CC)(C)C>C(O)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([N:13]3[CH2:14][CH2:15][N:16]([C:24]4[N:29]=[CH:28][N:27]=[C:26]5[NH:30][N:31]=[CH:32][C:25]=45)[CH2:17][CH2:18]3)=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:20])[F:21]
Reactant: Fc1ccc(-c2cnc(N3CCNCC3)[nH]2)cc1C(F)(F)F
Reactant: Clc1ncnc2[nH]ncc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Fc1ccc(-c2cnc(N3CCN(c4ncnc5[nH]ncc45)CC3)[nH]2)cc1C(F)(F)F
Yield: 79.7 %

Procedure:
Combine 1-[5-(4-Fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperazine (195 mg, 1.00 equiv; 0.620 mmoles); 4-Chloro-1H-pyrazolo[3,4-d]pyrimidine (1.00 equiv; 0.620 mmoles; 96 mg); isopropyl alcohol (3 mL); diisopropylethylamine (1 mL) and heat in a microwave reactor at 80° C. for 60 min. Evaporate the reaction mixture and purify on silica gel with 5% MeOH/DCM. Combine the fractions to give 213.2 mg (0.494 mmol, 80%) of 4-{4-[5-(4-Fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine. Dissolve the free base in DCM/MeOH and add 1.0 eq 1M HCl in ether. Concentrate the mixture to give 237.2 mg 4-{4-[5-(4-Fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine hydrochloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([S:11](=[O:15])(=[O:14])[CH2:12][CH2:13][N:7]3[C@H:6]3[CH2:16][CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][C@@H:5]23)[CH:10]=1.[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1B(O)O>>[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([S:11](=[O:15])(=[O:14])[CH2:12][CH2:13][N:7]3[C@H:6]3[CH2:16][CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][C@@H:5]23)[CH:10]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCS3(=O)=O
Product: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CCS3(=O)=O
Yield: 87.9 %

Procedure:
Tert-butyl(6bR,10aS)-5-(2,4-dichlorophenyl)-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate 3,3-dioxide (94 mg, 88%) was prepared via coupling of tert-butyl(6bR,10aS)-5-bromo-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate 3,3-dioxide (93 mg, 0.210 mmol) with 2,4-dichlorophenyl boronic acid (60 mg, 0.315 mmol) using the procedure described in Example 450 Step A. 1H NMR (CDCl3, 300 MHz) δ1.42 (s, 9H), 1.82-2.05 (m, 2H), 3.30-3.60 (m, 6H), 3.60-4.00 (m, 4H), 7.20-7.32 (m, 3H), 7.45 (s, 1H), 7.51 (s, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[Cl:12][C:13]([Cl:18])([Cl:17])[C:14](Cl)=[O:15]>ClCCl.CCN(CC)CC>[Cl:12][C:13]([Cl:18])([Cl:17])[C:14]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2)=[O:15]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Nc1cccc2cnccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc2cnccc12)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 65.1 %

Procedure:
A solution of 5-aminoisoquinoline (1.0 g, 6.9 mmol) in dichloromethane (40 mL) and Et3N (1 mL) at 5° C. was treated with trichloroacetyl chloride (1.38 g, 7.6 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 14 hours, concentrated, diluted with ethyl acetate and washed with 1N HCl. The aqueous layer was treated with aqueous NaHCO3 and extracted with ethyl acetate. The organic layer the was washed with water and concentrated. The solid residue was suspended in ethyl acetate (5 mL) and filtered to obtain 1.3 g (65%) of the title compound as a tan solid. 1H NMR (300 MHz, d6-DMSO) δ 11.20 (broad s, 1H), 9.41, (s, 1H), 8.60 (d, 1H), 8.18 (m, 1H), 7.77 (m, 2H), 7.77 (d, 1H); MS (DCI/NH3) m/z 289 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]CC2C=CC(OC)=CC=2)=[C:4]([O:18][CH3:19])[CH:3]=1.[F:20][C:21]([F:31])([F:30])[C:22](=O)[CH2:23][C:24]([O:26]CC)=O.OS(O)(=O)=O>C1C=CC=CC=1>[NH2:8][C:5]1[CH:6]=[C:7]2[C:2](=[CH:3][C:4]=1[O:18][CH3:19])[NH:1][C:24](=[O:26])[CH:23]=[C:22]2[C:21]([F:20])([F:30])[F:31]
Reactant: COc1ccc(CNc2ccc(N)cc2OC)cc1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: COc1cc2[nH]c(=O)cc(C(F)(F)F)c2cc1N

Procedure:
This compound was prepared according to General Method 11 (EXAMPLE 22) from (4-amino-2-methoxyphenyl)-(4-methoxybenzyl)amine (1.23 g, 4.76 mmol) and ethyl 4,4,4-trifluoroacetoacetate (1.05 g, 5.71 mmol) in 60 mL benzene followed by treatment with 10 mL concentrated H2SO4 to afford 0.734 (60%) of 6-amino-7-methoxy-4-(trifluoromethyl)-1H-quinolin-2-one, a yellow solid, after rinsing with MeOH:ether:hexanes. Data for 6-amino-7-methoxy-4-(trifluoromethyl)-1H-quinolin-2-one: Rf 0.28 (19:1 CH2Cl2:MeOH); 1H NMR (500 MHz, CDCl3) δ 12.2 (v broad s, 1H), 7.06 (broad s, 1H), 6.93 (s, 1H), 6.79 (s, 1H), 4.01 (s, 3H), 3.94 (broad s, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:17][CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=31)[C:9]1[C:4]2=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[S:24]([O:1][CH2:2][C:3]12[CH2:17][CH:10]([C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=31)[C:11]1[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC12CC(c3ccccc31)c1ccccc12
Product: Cc1ccc(S(=O)(=O)OCC23CC(c4ccccc42)c2ccccc23)cc1

Procedure:
9-Tosyloxymethyl-9,10-dihydro-9,10-methanoanthracene is prepared from 9-hydroxymethyl-9,10-dihydro-9,10-methanoanthracene by treatment with p-toluenesulfonyl chloride in the presence of a base in an inert solvent;
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.Br[CH2:30][CH:31]1[CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C>[CH:31]1([CH2:30][N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)[CH2:33][CH2:32]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC2CC2)c2ncnn12
Temperature: 70 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), (bromomethyl)cyclopropane (0.16 mL), potassium carbonate (0.38 g) and N,N-dimethylacetamide (10 mL) was stirred at 70° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.54 g, 93%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:19]([NH:29]C(=O)OC(C)(C)C)[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)=[N:4][CH:5]=[C:6]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH:7]=1.[ClH:37].O1CCOCC1>CO>[ClH:37].[NH2:29][C@H:19]([C:3]1[N:4]=[CH:5][C:6]([N:8]2[C:9](=[O:18])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]2=[O:17])=[CH:7][C:2]=1[Br:1])[CH2:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1ncc(N2C(=O)c3ccccc3C2=O)cc1Br
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@@H](Cc1cc(F)cc(F)c1)c1ncc(N2C(=O)c3ccccc3C2=O)cc1Br
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Compound 30E (260 mg, 0.047 mmol) was dissolved in 10 mL of methanol and cooled to 0° C. To it was added 4N HCl/1,4-dioxane (2 ml). The reaction mixture was stirred at room temperature for overnight and concentrated to afford the title product. MS (m/z) 458.00 [M+H]+