Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[CH3:23][C:24]1[S:25][C:26]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)=[C:27]([C:29](O)=[O:30])[N:28]=1>>[CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][N:6]([C:29]([C:27]3[N:28]=[C:24]([CH3:23])[S:25][C:26]=3[C:32]3[CH:33]=[CH:34][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:36][CH:37]=3)=[O:30])[C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Reactant: Cc1nc(C(=O)O)c(-c2ccc(C(F)(F)F)cc2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-(4-trifluoromethyl-phenyl)thiazole-4-carboxylic acid.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[C:13]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)#[N:14]>ClCCl>[Br:2][CH2:3][CH2:4][NH:5][S:21]([C:18]1[CH:17]=[CH:16][C:15]([C:13]#[N:14])=[CH:20][CH:19]=1)(=[O:23])=[O:22]
Reactant: NCCBr
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(S(=O)(=O)NCCBr)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
To an ice cooled solution of 2-bromoethylamine hydrogenbromide (12.2 g, 0.0595 mol) in dry dichloromethane (100 mL) was added triethylamine and the mixture stirred for 15 min. 4-Cyanobenzenesulfonyl chloride (10 g, 0.0486 mol) in dichloromethane was added, dropwise. Stirring was continued at RT for 1 h. The reaction mixture was diluted with dichloromethane, washed with water, followed by brine, then dried over sodium sulfate. Solvents were evaporated and the residue crystallized from petroleum ether to give 12.5 g of the sub-title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][CH2:12][C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[C:6]1=[O:15])=[O:4].[H][H]>CO.[Pt]=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][CH2:12][C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]1[OH:15])=[O:4]
Reactant: COC(=O)C1CCCC2(CCCC2)C1=O
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: COC(=O)C1CCCC2(CCCC2)C1O
Yield: 100.2 %

Procedure:
To a solution of 6-oxo-spiro[4.5]decane-7-carboxylic acid methyl ester (9.99 g) obtained in Step 2 in methanol (200 mL) was added platinum oxide (0.2 g) in an atmosphere of hydrogen (<0.3 Mpa) at room temperature overnight. Then, the reaction mixture was filtered through Celite and the filtrate was concentrated. After adding ethyl acetate (30 mL) and n-hexane (30 mL) to the residue, the resulting insolubles were filtered off. The filtrate was concentrated and then dried in vacuo to give 6-hydroxy-spiro[4.5]decane-7-carboxylic acid methyl ester (10.11 g).
Reaction SMILES: C1[O:14][C:4]([CH3:13])([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)OC1.[O-]CC.[Na+].Cl.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26]Cl>C(O)C>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][O:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C:4](=[O:14])[CH3:13])=[CH:11][CH:10]=1
Reactant: ClCc1ccccn1
Reactant: CC1(Cc2ccc(O)cc2)OCCO1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Cc1ccc(OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of (4-hydroxyphenyl)propan-2-one ethylene ketal (28 g) in ethanol (40 ml) was added to a stirred solution of sodium ethoxide in ethanol (7.1 g of sodium in 100 ml) and the resulting solution stirred at room temperature for 20 minutes. A suspension of 2-picolyl chloride hydrochloride (25 g) in ethanol (60 ml) was added and the resulting mixture was boiled under reflux for 5 hours, cooled and filtered. 2M Hydrochloric acid (100 ml) was added, the solution boiled for 5 h, cooled and neutralised with 2M sodium hydroxide solution. After dilution with water the solution was extracted with dichloromethane and the washed organic phase dried and evaporated to give a dark oil. Bulb to bulb distillation gave [4-(2-pyridylmethyloxy)phenyl]propan-2-one, b.pt. 96°-100° C./0.2 mm, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:19]=1)/[CH:7]=[CH:8]/[C:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=2[S:11][CH:10]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>C1COCC1.C(OCC)(=O)C>[NH2:18][C:17]1[C:12]2[S:11][CH:10]=[C:9](/[CH:8]=[CH:7]/[C:6]3[CH:19]=[C:2]([NH:1][C:26](=[O:27])[C:25]4[CH:29]=[CH:30][CH:31]=[C:23]([C:22]([F:21])([F:32])[F:33])[CH:24]=4)[CH:3]=[CH:4][C:5]=3[CH3:20])[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: Cc1ccc(N)cc1/C=C/c1csc2c(N)ncnc12
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1/C=C/c1csc2c(N)ncnc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.8 %

Procedure:
(E)-7-(5-amino-2-methylstyryl)thieno[3,2-d]pyrimidine-4-amine (100 mg, 0.354 mmol) was dissolved in anhydrous THF, TEA (0.1 mL, 0.709 mmol) and 3-(trifluoromethyl)benzoyl chloride (81 mg, 0.390 mmol) were added thereto at room temperature and stirred for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried with MgSO4, filtered and concentrated. The resulting mixture was purified by silica gel chromatography to obtain the title compound (138 mg, 86% yield) (see Table 1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1([F:27])[CH2:17][CH2:16][C:15]([CH2:25][NH2:26])([C:18]2[CH:19]=[N:20][C:21]([CH3:24])=[N:22][CH:23]=2)[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:26][CH2:25][C:15]1([C:18]2[CH:23]=[N:22][C:21]([CH3:24])=[N:20][CH:19]=2)[CH2:16][CH2:17][C:12]([F:11])([F:27])[CH2:13][CH2:14]1)=[O:6]
Reactant: Cc1ncc(C2(CN)CCC(F)(F)CC2)cn1
Reactant: O=C(O)c1ccccc1Cl
Product: Cc1ncc(C2(CNC(=O)c3ccccc3Cl)CCC(F)(F)CC2)cn1

Procedure:
From 2-chlorobenzoic acid and C-[4,4-difluoro-1-(2-methyl-pyrimidin-5-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=380.1, tR (minutes, Method F)=2.37
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]3[C:17]=2[CH2:18][C:19](O)=[O:20])=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][NH:29][CH2:30][CH3:31].Cl.C(OCC)C>ClCCl>[ClH:1].[CH2:30]([N:29]([CH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=1)[C:19](=[O:20])[CH2:18][C:17]1[N:11]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]2=[N:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH3:31]
Reactant: CCNCc1ccccn1
Reactant: Cc1ccn2c(CC(=O)O)c(-c3ccc(Cl)cc3)nc2c1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCN(Cc1ccccn1)C(=O)Cc1c(-c2ccc(Cl)cc2)nc2cc(C)ccn12
Yield: 51.2 %

Procedure:
According to the method of Example 13, 2-(4-chlorophenyl)-7-methylimidazo[1,2-a]pyridine-3-acetic acid and N-(2-pyridinylmethyl)ethylamine were used as raw materials for synthesis, salified with hydrochloric acid-ethyl ether solution in dry dichloromethane, then crystallized with methanol-tetrahydrofuran to obtain a corresopnding hydrochloride pure product. Yellow solid powder, yield 51.2%. m.p. 178-180° C., ESI-MS m/z: 420[M+H]+, 1H NMR(D2O, 400 MHz)δ: 0.95(t, 0.5H, J=7.00 Hz), 1.14(t, 2.5H, J=7.00 Hz), 2.38(s, 2.5H), 2.40(s, 0.5H), 3.30(q, 0.4H, J=7.00 Hz), 3.56(q, 1.6H, J=7.00 Hz), 4.14(s, 0.4H), 4.36(s, 1.6H), 4.76(s, 1.6H), 4.86(s, 0.4H), 7.14-7.24(m, 1H), 7.30-7.46(m, 4H), 7.50(s, 1H), 7.69-7.75(m, 2H), 8.11-8.13(m, 1H), 8.33-8.53(m, 2H).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([Cl:29])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:19]=1>>[N:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[CH:28]=[C:27]([Cl:29])[S:26][C:16]=3[N:17]=2)=[CH:25][CH:24]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Clc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: Clc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-methylenedioxyphenethylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].Cl[CH2:18][C:19]1[N:20]=[CH:21][S:22][CH:23]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([C:11]2[CH:16]=[N:15][CH:14]=[N:13][CH:12]=2)[CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: ClCc1cscn1
Reactant: O=[N+]([O-])c1ccc(Nc2cncnc2)nc1
Product: O=[N+]([O-])c1ccc(N(Cc2cscn2)c2cncnc2)nc1

Procedure:
Starting compounds: 5-[N-(5-nitro-2-pyridyl) amino]pyrimidine and 4-chloromethylthiazole
Reaction SMILES: [NH:1]([C:8]1[C:13]([CH2:14][O:15][CH2:16][CH3:17])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([OH:32])[CH2:28][N:29]([CH3:31])[CH3:30])=[CH:21][CH:20]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1[CH:38]=[C:37](C)[O:36][N:35]=1.Cl>CN1C(=O)CCC1>[NH:1]([C:8]1[C:13]([CH2:14][O:15][C:16]2[CH:17]=[C:37]([CH3:38])[O:36][N:35]=2)=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH:27]([OH:32])[CH2:28][N:29]([CH3:31])[CH3:30])=[CH:23][CH:24]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCc1cnc(Nc2ccc(OCC(O)CN(C)C)cc2)nc1Nc1ccccc1
Reactant: Cc1cc(O)no1
Agent: Cl
Solvent: CN1CCCC1=O
Product: Cc1cc(OCc2cnc(Nc3ccc(OCC(O)CN(C)C)cc3)nc2Nc2ccccc2)no1
Temperature: 100 °C
Yield: 43.4 %

Procedure:
4-Anilino-5-(ethoxymethyl)-2-{4-[2-hydroxy-3-(N,N-dimethylamino)propoxy]anilino}pyrimidine (Example 86, 100 mg, 0.23 mmol) was dissolved in NMP (2 ml). 3-Hydroxy-5-methylisoxazole (45 mg, 0.46 mmol) and ethereal hydrogen chloride (1.0M; 0.46 ml, 0.46 mmol) were added, and the solution was heated at 100° C. for 20 hours. Volatile material was removed by evaporation, and the residue was dissolved in 10% methanol solution in DCM (3 ml) and loaded on a Varian Mega Bond Elut column. The column was eluted with 0-2.5% methanol solution in DCM containing 0.5% aqueous ammonia solution. Concentration of the appropriate fractions and trituration of the residue with diethyl ether gave the product as a white crystalline solid (49 mg, 44%). NMR: 2.17 (s, 6H), 2.22 (s, 3H), 2.2-2.45 (m, 2H), 3.75-3.9 (m, 3H), 4.73 (br s, 1H), 4.49 (s, 2H), 5.78 (s, 1H), 6.80 (d, 2H), 7.02 (t, 1H), 7.30 (dd, 2H), 7.50 (d, 2H), 7.70 (d, 2H) 8.04 (s, 1H), 8.76 (s, 1H), 9.05 (s, 1H); MS (MH+): 491.5.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:10]1[S:11][C:12]([S:61][CH3:62])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([NH:31][C:32]([NH:41]C(OC(C)(C)C)=O)=[N:33]C(OC(C)(C)C)=O)=[CH:26][C:25]=3[NH:49][C:50]([NH:52][CH2:53][CH2:54][CH2:55][CH2:56][S:57]([CH3:60])(=[O:59])=[O:58])=[O:51])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])(C)(C)C.[F:64][C:65]([F:70])([F:69])[C:66]([OH:68])=[O:67]>C(Cl)Cl>[F:64][C:65]([F:70])([F:69])[C:66]([OH:68])=[O:67].[NH:31]([C:27]1[CH:28]=[C:29]([CH3:30])[C:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([C:13]3[CH:14]=[C:10]([C:8]([NH2:9])=[NH:7])[S:11][C:12]=3[S:61][CH3:62])(=[O:16])=[O:17])[CH:19]=2)=[C:25]([NH:49][C:50]([NH:52][CH2:53][CH2:54][CH2:55][CH2:56][S:57]([CH3:60])(=[O:59])=[O:58])=[O:51])[CH:26]=1)[C:32]([NH2:41])=[NH:33]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2NC(=O)NCCCCS(C)(=O)=O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cc(NC(=N)N)cc2NC(=O)NCCCCS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a flask charged with [(4-{4′-(N′,N″-di-tert-butoxycarbonyl-guanidino)-2′-[3-(4-methanesulfonyl-butyl)-ureido]-6′-methyl-biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophen-2-yl)-imino-methyl]-carbamic acid tert-butyl ester (110 mg, 0.116 mmol) was added a solution of trifluoroacetic acid in DCM (3.0 mL, 50%) and stirred at ambient temperature for 1 h. The mixture was concentrated, and purified by HPLC (C18-column, 5–50% CH3CN in H2O over 15 min.) to give the title compound (63 mg, 62% yield) as a white solid.
Reaction SMILES: NN.CC(C)(C)[CH2:5][O:6][C:7]1[C:8](=[O:27])[C:9]2[C:14]([C:15](=[O:23])[C:16]=1[O:17][CH2:18]C(C)(C)C)=[C:13]([N+:24]([O-])=O)[CH:12]=[CH:11][CH:10]=2>[Pd].C(O)C>[CH3:5][O:6][C:7]1[C:8](=[O:27])[C:9]2[C:14]([C:15](=[O:23])[C:16]=1[O:17][CH3:18])=[C:13]([NH2:24])[CH:12]=[CH:11][CH:10]=2
Reactant: CC(C)(C)COC1=C(OCC(C)(C)C)C(=O)c2c(cccc2[N+](=O)[O-])C1=O
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: COC1=C(OC)C(=O)c2c(N)cccc2C1=O
Yield: 82.8 %

Procedure:
Hydrazine (4.0 ml, 125 mmol of 97%) was added dropwise, over a 2 hour period, to a stirred mixture of the captioned compound of Preparation 2 (19.9 g, 75.6 mmol), 5% palladium on carbon (10 g) and ethanol (750 ml) in a nitrogen atmosphere. The catalyst was filtered off through a celite pad that was washed with hot ethanol (2×300 ml). The combined filtrate and washings were concentrated to dryness in vacuo and the residue recrystallized from water:ethanol (1.5:1) giving 14.6 g of 2,3-dimethoxy-5-amino-1,4-naphthoquinone, mp 116°-117°.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[N:9]1([C:16]2[N:21]=[C:20]([NH2:22])[N:19]3[N:23]=[C:24]([C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[C:18]3[N:17]=2)[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CCN(CC)CC>CC#N>[O:27]1[CH:28]=[CH:29][CH:30]=[C:26]1[C:24]1[CH:25]=[C:18]2[N:17]=[C:16]([N:9]3[CH2:15][CH2:14][CH2:13][N:12]([CH2:2][C:3]4[CH:7]=[C:6]([CH3:8])[O:5][N:4]=4)[CH2:11][CH2:10]3)[N:21]=[C:20]([NH2:22])[N:19]2[N:23]=1
Reactant: Nc1nc(N2CCCNCC2)nc2cc(-c3ccco3)nn12
Reactant: Cc1cc(CCl)no1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(CN2CCCN(c3nc(N)n4nc(-c5ccco5)cc4n3)CC2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Chloromethyl-5-methyl-isoxazole (1.5 eq.) was directly added to a solution of 2-[1,4]diazepan-1-yl-7-furan-2-yl-pyrazolo[1,5-a][1,3,5]triazin-4-ylamine (0.14 mmol) and Et3N (0.3 mmol) in 3 mL of CH3CN. The resulting reaction mixture was stirred at room temp for 18 hours. It was then concentrated and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 7.90 (br s, 2 H), 7.80 (d, J=1.0 Hz, 1H), 7.05 (d, J=3.6 Hz, 1H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H), 6.30 (s, 1H), 3.65 (m, 2H), 3.20-2.75 (m, 10 H), 2.35 (s, 3H) ppm. MS: m/z: 395 [M+H]+.
Reaction SMILES: O/C=[C:3]1/[C:4](=[O:11])[CH2:5][CH2:6][C:7]([CH3:10])([CH3:9])[CH2:8]/1.F[B-](F)(F)F.[CH2:17]([O:19][CH+:20][O:21][CH2:22][CH3:23])[CH3:18]>>[CH2:17]([O:19][CH:20]([O:21][CH2:22][CH3:23])[CH:3]1[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][CH2:5][C:4]1=[O:11])[CH3:18]
Reactant: CCO[CH+]OCC
Reactant: CC1(C)CCC(=O)/C(=C/O)C1
Agent: F[B-](F)(F)F
Product: CCOC(OCC)C1CC(C)(C)CCC1=O

Procedure:
Another route involves reacting dimethylcyclohexanone (1A) with a prepared solution of diethoxycarbenium fluoroborate to provide 2-(diethoxymethyl)-4,4-dimethylcyclohexanone (8). The reaction is typically performed below room temperature in a solvent such as but not limited to methylene chloride. Chlorophenyl magnesium bromide is then added to a solution of 2-(diethoxymethyl)-4,4-dimethylcyclohexanone (8) to provide 1-(4-chlorophenyl)-2-(diethoxymethyl)-4,4-dimethylcyclohexanol (9). The reaction is typically performed below room temperature in a solvent such as but not limited to tetrahydrofuran. 1-(4-Chlorophenyl)-2-(diethoxymethyl)-4,4-dimethylcyclohexanol (9) can be treated with an acid such as but not limited to HCl, to provide the aldehyde intermediate (2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde) (4).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9].[O:10]=[C:11]1[NH:19][CH:18]=[N:17][C:16]2[N:15]([CH2:20][CH2:21][C:22](OCC)=[O:23])[CH:14]=[N:13][C:12]1=2>C(#N)C>[O:10]=[C:11]1[NH:19][CH:18]=[N:17][C:16]2[N:15]([CH2:20][CH2:21][C:22]([NH:1][CH2:2][CH2:3][CH:4]3[CH2:8][CH2:7][CH2:6][N:5]3[CH3:9])=[O:23])[CH:14]=[N:13][C:12]1=2
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Reactant: CN1CCCC1CCN
Solvent: CC#N
Product: CN1CCCC1CCNC(=O)CCn1cnc2c(=O)[nH]cnc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.565 g (4.41 mmol) of 2-(2-aminoethyl)-1-methylpyrrolidine was added to a 10 ml round bottom flask equipped with a magnetic stirring bar. The solution was heated and 0.250 g (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) was added and the solution was heated at 110°-120° C. for two hours. The orange solution was allowed to cool to room temperature and 8 ml acetonitrile was added and the solution was stirred for 20 minutes to wash the solid. The solution was filtered by Buchner vacuum filtration and the solid was washed with acetonitrile and then with ether. Upon drying 265 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]propanamide (AIT-0045) as a white solid was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(OC([NH:23][C@@H:24]([CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[C:25](O)=[O:26])=O)(C)(C)C>>[NH2:23][C@@H:24]([CH2:28][O:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1)[C:25]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)=[O:26]
Reactant: Nc1ccc(Oc2ccc(Br)cc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccc(F)cc1)C(=O)O
Product: N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(Br)cc2)cc1
Yield: 50 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(4-bromophenoxy)aniline and (S)-2-(tert-butoxycarbonylamino)-3-(4-fluorobenzyloxy)propanoic acid, gave (S)-2-amino-N-(4-(4-bromophenoxy)phenyl)-3-(4-fluorobenzyloxy)propanamide (200 mg, 50%).
Reaction SMILES: [C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH2:15])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([CH2:29][C:30]([NH:15][C:14]2[N:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:22]=[C:10]3[CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:13]=2)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Product: O=C(Cc1ccccc1)Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12

Procedure:
The title compound, MS m/e (%): 406 (M+H+, 100), was prepared in accordance with the general method of example 31 from 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine and phenylacetyl chloride.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.N1([NH:28][S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34](Br)[CH:33]=2)(=[O:31])=[O:30])CCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.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>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH2:16][CH2:15][C@@H:2]([OH:1])[C@@H:3]([O:4][C:5]2[CH:10]=[CH:9][C:8]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([S:29]([N:28]4[CH2:14][CH2:3][CH2:2][CH2:15]4)(=[O:30])=[O:31])[CH:37]=3)=[CH:7][CH:6]=2)[CH3:14])[CH:18]=1
Reactant: O=S(=O)(NN1CCCC1)c1cccc(Br)c1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
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: CCO
Product: C[C@H](Oc1ccc(-c2cccc(S(=O)(=O)N3CCCC3)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 117.9 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.150 g, Example 33), 3-bromobenzenesulfonic acid, pyrrolidinyl amide (0.290 g), 2M aqueous sodium carbonate (0.50 ml) and tetrakis(triphenylphosphine)palladium(0) (0.025 g) in ethanol (3 ml). The reaction mixture was heated at 90° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure, taken up in ethanol and concentrated again (twice). The residue was triturated with acetone and then filtered through silica gel. The filtrate was concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give a gum, which was further purified by reverse-phase HPLC to give the title compound as a foam (0.137 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[CH:7][N:6]=1)=[O:4].[OH-].[Li+]>C1COCC1.CO>[CH3:11][C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)[CH:9]=1
Reactant: COC(=O)c1ncc(-c2cccc(C(F)(F)F)c2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)cnc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.3 %

Procedure:
To a solution of 1.00 g (3.4 mmol) of 3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid methyl ester in 40 ml of THF/MeOH (1:1) was added 8.47 ml (8.5 mmol) of lithium hydroxide solution (1 molar in water) and the reaction mixture was stirred at RT. After 20 hours, the solvents were evaporated and the residue poured into crashed ice, the pH was adjusted to 1-2 with HCl 1N and the reaction mixture was extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by re-crystallization from CH2Cl2/heptane to give 0.94 g (99%) of the title compound as colorless solid. MS: 280.0 (M−H−).
Reaction SMILES: F[C:2](F)(F)C1C=C(C=C(C(F)(F)F)C=1)CN(C1CCCNC2C(C)=CC(C(F)(F)F)=CC1=2)C(=O)C.[CH:36]([O:39][C:40]([N:42]1[C:48]2[C:49]3[CH2:50][CH2:51][CH2:52][C:53]=3[C:54](Br)=[CH:55][C:47]=2[CH:46]([N:57]([C:73](=[O:75])[CH3:74])[CH2:58][C:59]2[CH:64]=[C:63]([C:65]([F:68])([F:67])[F:66])[CH:62]=[C:61]([C:69]([F:72])([F:71])[F:70])[CH:60]=2)[CH2:45][CH2:44][CH2:43]1)=[O:41])([CH3:38])[CH3:37]>>[CH:36]([O:39][C:40]([N:42]1[C:48]2[C:49]3[CH2:50][CH2:51][CH2:52][C:53]=3[C:54]([CH3:2])=[CH:55][C:47]=2[CH:46]([N:57]([C:73](=[O:75])[CH3:74])[CH2:58][C:59]2[CH:64]=[C:63]([C:65]([F:68])([F:67])[F:66])[CH:62]=[C:61]([C:69]([F:72])([F:71])[F:70])[CH:60]=2)[CH2:45][CH2:44][CH2:43]1)=[O:41])([CH3:38])[CH3:37]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c1cc(Br)c1c2CCC1
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCNc2c(C)cc(C(F)(F)F)cc21
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c1cc(C)c1c2CCC1

Procedure:
The titled compound was prepared in a manner analogous to the procedure for the preparation of N-(3,5-Bis-trifluoromethyl-benzyl)-N-(9-methyl-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-acetamide (example 123, step 3) by replacing N-(3,5-Bis-trifluoromethyl-benzyl)-N-(9-bromo-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-acetamide with (+/−)-6-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-4-bromo-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylic acid isopropyl ester (example 144, step 2)