Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[S:21]1[C:25]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)=[CH:24][N:23]=[CH:22]1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:25]3[S:21][CH:22]=[N:23][CH:24]=3)[CH:27]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2cncs2)c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2cncs2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 3-(thiazol-5-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.79 min.; [M+H]+: 408.98 g/mol.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]=2[CH:17]=1)C=C.CN1C[CH2:22][CH2:21][C:20]1=O>>[OH:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]=2[C:17]=1[CH2:22][CH:21]=[CH2:20]
Reactant: CN1CCCC1=O
Reactant: C=CCOc1ccc2oc(C(=O)OC)cc2c1
Product: C=CCc1c(O)ccc2oc(C(=O)OC)cc12

Procedure:
A mixture of methyl 5-hydroxybenzofuran-2-carboxylate (4.14 g), potassium carbonate (5.95 g) and allyl bromide (3.73 ml) in dry acetone (100 ml) was refluxed and stirred for 16 hours. The solvent was evaporated and the residue was partitioned between water and ether. The ether was washed with water, dried and evaporated to give methyl 5-(prop-2-enyloxy)benzofuran-2-carboxylate (4.7 g) as a solid, characterised by NMR and mass spectral data. This ester (3.74 g) in N-methylpyrrolidinone (30 ml) was refluxed under nitrogen for 2 hr, cooled, and partitioned between water and ethyl acetate. The organic phase was washed with water, dried and evaporated to give the title ester (3.5 g), mp 114°-119°.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.Cl[CH2:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.[H-].[Na+].[I-].[Na+]>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:22][CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:18][CH:19]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: ClCCCN1CCCC1
Reactant: COCCc1cc2ccccc2n1-c1ccc(O)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCc1cc2ccccc2n1-c1ccc(OCCCN2CCCC2)cc1
Temperature: 70 °C
Yield: 47.4 %

Procedure:
4-[2-(2-Methoxyethyl)indol-1-yl]phenol (0.39 mmol) was dissolved in N,N-dimethylformamide (4 mL), and 1-(3-chloropropyl)pyrrolidine (58 mg, 0.39 mmol), sodium hydride (19 mg, 60% dispersion in mineral oil, 0.47 mmol), and sodium iodide (59 mg, 0.39 mmol) were added. The reaction was heated at 70° C. for 1.5 hours, then carefully quenched with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography to give 70 mg of the desired product. LC-MS (C24H30N2O2 calc'd 378) m/z 379 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.60-7.56 (m, 1H), 7.25-7.21 (m, 2H), 7.10-7.00 (m, 5H), 6.45 (s, 1H), 4.11 (t, J=6.3 Hz, 2H), 3.57 (t, J=7.2 Hz, 2H), 3.30 (s, 3H), 2.89 (t, J=7.2 Hz, 2H), 2.74 (t, J=7.5 Hz, 2H), 2.65 (m, 4H), 2.16-2.05 (m, 2H), 1.90-1.81 (m, 4H).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][C:7]([C:11]([F:14])([F:13])[F:12])([OH:10])[CH2:6][CH2:5]1)[C:2]#[CH:3].[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[O:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]2[CH:30]=[C:31](I)[S:32][C:25]=12)[NH2:19]>>[NH2:19][C:18]1[CH:20]=[CH:21][C:22]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]3[CH:30]=[C:31]([C:3]#[C:2][CH2:1][N:4]4[CH2:9][CH2:8][C:7]([C:11]([F:14])([F:12])[F:13])([OH:10])[CH2:6][CH2:5]4)[S:32][C:25]=23)=[C:16]([F:15])[CH:17]=1
Reactant: C#CCN1CCC(O)(C(F)(F)F)CC1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Product: Nc1ccc(Oc2ccnc3cc(C#CCN4CCC(O)(C(F)(F)F)CC4)sc23)c(F)c1
Temperature: 50 °C
Yield: 39.7 %

Procedure:
Prepared from 1-(prop-2-ynyl)-4-(trifluoromethyl)piperidin-4-ol (40 mg, 0.19 mmol) and 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 50 mg, 0.13 mmol) according to the procedure described for Example 6, Step B, except the reaction was heated at 50° C. for 7 hours. The crude was partially purified by preparative TLC [5% MeOH (containing 7N NH3) in CH2Cl2]. The product was obtained as a waxy solid (24 mg) and carried forward without further purification,
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>>[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)=[CH:23][CH:22]=1
Reactant: Cc1ccc(CN)cc1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: Cc1ccc(CNc2nccc(-n3cnc4ccccc43)n2)cc1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 4-methylbenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 316.1 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.60 (s, 1H); 8.41 (br s, 1H); 8.09 (br s, 1H); 7.86 (m, 1H); 7.20 (d, J=8.0 Hz, 1H); 6.83 (d, J=5.3 Hz, 1H); 5.80 (br s, 1H); 4.71 (d, J=5.8 Hz, 2H); 2.37 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2=[N:9][C@@H:10]([CH2:24][C:25]([O:27]C)=[O:26])[C:11]3[N:12]([C:20]([CH3:23])=[N:21][N:22]=3)[C:13]3[S:17][C:16]([CH3:18])=[C:15]([CH3:19])[C:14]2=3)=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2=[N:9][C@@H:10]([CH2:24][C:25]([OH:27])=[O:26])[C:11]3[N:12]([C:20]([CH3:23])=[N:21][N:22]=3)[C:13]3[S:17][C:16]([CH3:18])=[C:15]([CH3:19])[C:14]2=3)=[CH:6][CH:7]=1
Reactant: COC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2c(sc(C)c2C)-n2c(C)nnc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)O)c1nnc(C)n1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
Methyl 2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate (see e.g., WO 2006129623) (100.95 mg, 0.243 mmol was suspended in 1 mL methanol to which was added a freshly prepared solution of lithium hydroxide monohydrate (0.973 mL, 0.5 M, 0.487 mmol) and shaken at ambient temperature for 3 hours. The methanol was evaporated and the pH adjusted with aqueous hydrochloric acid (1 M, 0.5 mL, 0.5 mmol) and extracted four times with ethyl acetate. The combined ethyl acetate layers were dried over magnesium sulfate and evaporated to afford 2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (85.3 mg, 87.0%); ESI-MS m/z=401.1 [(M+H)+] which was used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[CH:17][N:18]([CH3:20])[CH3:19])[C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1.N1C[CH2:26][O:25][CH2:24]C1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[CH:17][N:18]3[CH2:19][CH2:26][O:25][CH2:24][CH2:20]3)[C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: CN(C)C=C1C(=O)N(c2cccc(Cl)c2)c2ccccc21
Solvent: CCO
Product: O=C1C(=CN2CCOCC2)c2ccccc2N1c1cccc(Cl)c1
Reaction time: 18 h

Procedure:
Title product of Example A3 (0.3 g, 1.0 mmole), morpholine (0.45 ml, 5 mmole) and ethanol (10 ml) were combined and stirred 18 hours at 25°. Additional morpholine (2 ml) was added and the mixture refluxed 4 hours. The reaction mixture was evaporated in vacuo to an oil, chromatographed on silica gel (4.5 cm×18 cm) eluting with ethyl acetate, initially isolating purified title product as an oil which crystallized on standing under ether/pentane, 0.27 g; m.p. 130°-132.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[C:5]([F:13])=[CH:4][N:3]=1.[CH3:14][O:15][C:16](=[O:29])[CH:17]([N:19]1[C:27]2[C:22](=[CH:23][C:24](O)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1)[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>ClCCl.CCOC(C)=O>[CH3:14][O:15][C:16](=[O:29])[CH:17]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([O:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]3[C:5]([F:13])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1)[CH3:18]
Reactant: OCCCNc1nc(Cl)ncc1F
Reactant: COC(=O)C(C)n1ccc2cc(O)ccc21
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C(C)n1ccc2cc(OCCCNc3nc(Cl)ncc3F)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.3 %

Procedure:
To a solution of 3-(2-chloro-5-fluoro-pyrimidin-4-ylamino)-propan-1-ol (Example 80, 0.66 g, 3.20 mmol) and 2-(5-hydroxy-indol-1-yl)-propionic acid methyl ester (Example 7, 0.47 g, 2.13 mmol) in dichloromethane (10.80 mL) was added triphenylphosphine (0.85 g, 3.20 mmol) and 1,1′-(azodicarbonyl)-dipiperidine (0.82 g, 3.20 mmol) under argon. The golden yellow mixture was stirred at rt for 18 h. The desired product (0.54 g, 59%) was obtained after column chromatography (67% hexanes in EtOAc). 1H NMR (300 MHz, CD3OD) δ 7.85 (d, 1H), 7.27-7.06 (m, 3H), 6.82-6.79 (m, 1H), 6.40 (d, 1H), 5.24 (q, 1H), 4.11-4.07 (m, 2H), 3.70-3.67 (m, 5H), 2.15-2.09 (m, 2H), 1.77 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]=[CH:11][C:10]=1[NH2:20].NC1C=CC(C)=CC=1[C:24](O)=[O:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:9]2[C:18]3[CH:17]=[C:16]([CH3:19])[CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[NH:20][C:24]1=[O:25]
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: Cc1ccc2ncc(N)c(Nc3ccccc3Cl)c2c1
Product: Cc1ccc2ncc3[nH]c(=O)n(-c4ccccc4Cl)c3c2c1

Procedure:
The title compound os obtained as described for Example 92 using N4-(2-chloro-phenyl)-6-methyl-quinoline-3,4-diamine, which is obtained as described for Example 92, steps a=to e) using 2-amino-5-methyl-benzoic acid (Fluka, Buchs, Switzerland) as starting material. Title compound: Analytical HPLC: tret=5.80 min (Grad. 2); ES-MS: m/e0=310.1, 312.1.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2/[CH:12]=[CH:13]/[C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:19](CC)CC)C.C(Cl)(=O)OCC.N>O.O1CCCC1>[C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2/[CH:12]=[CH:13]/[C:14]([NH2:19])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)/C=C/c1cnoc1-c1ccccc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)/C=C/c1cnoc1-c1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a mixture of (E)-3-(5-phenyl-4-isoxazolyl)propenoic acid (0.97 g), triethylamine (1 ml) and tetrahydrofuran (60 ml) was added ethyl chlorocarbonate (0.5 ml) at −30° C. and the mixture was stirred at −20° C. for 1 hr. To the obtained mixture was added aqueous ammonia (1 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated to give (E)-3-(5-phenyl-4-isoxazolyl)propenamide (0.86 g, yield 89%) as colorless crystals. The crystals were recrystallized from acetone-hexane. melting point: 194–196° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][C:3]=1[Cl:11].[CH3:12][NH2:13]>C(O)C>[Cl:11][C:3]1[CH:4]=[C:5]([NH:8][C:9]([NH:13][CH3:12])=[S:10])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CN
Solvent: CCO
Product: CNC(=S)Nc1ccc(Cl)c(Cl)c1
Temperature: 80 °C

Procedure:
To a stirred solution of 1,2-dichloro-4-isothiocyanatobenzene (1 g, 4.9 mmol) in ethanol (30 mL) was added 8M methyl amine in ethanol (0.613 mL, 4.9 mmol) and the reaction was heated at 80° C. overnight. The solvent was removed under vacuum and the residue was washed with diethyl ether (10 mL) and dried to give crude 1-(3,4-dichlorophenyl)-3-methylthiourea as an off white solid (0.8 g, 69%). 1HNMR: 400 MHz, DMSO-d6: δ 2.93 (d, J=4.40 Hz, 3H), 7.37 (d, J=7.60 Hz, 1H), 7.55 (d, J=8.40 Hz, 1H), 7.86 (d, J=2.40 Hz, 1H), 7.92 (bs, 1H), 9.74 (bs, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[N:7]=[C:8]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH3:16])=[CH:11]2.CC1(C)C(C)(C)OB([C:46]2[CH:51]=[CH:50][C:49]([CH2:52][C:53]([O:55][CH2:56][CH2:57][CH3:58])=[O:54])=[CH:48][CH:47]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O.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:32]([O:31][C:30]([NH:29][C:8]1[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:26])([CH3:25])[CH3:27])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH3:16])=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([C:46]3[CH:51]=[CH:50][C:49]([CH2:52][C:53]([O:55][CH2:56][CH2:57][CH3:58])=[O:54])=[CH:48][CH:47]=3)=[CH:37][C:6]=2[N:7]=1)=[O:36])([CH3:34])([CH3:35])[CH3:33]
Reactant: CCCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
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: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCOC(=O)Cc1ccc(-c2ccc3c(c2)N=C(NC(=O)OC(C)(C)C)CC(C(=O)N(CCC)CCCO[Si](C)(C)C(C)(C)C)=C3)cc1
Temperature: 100 °C

Procedure:
tert-butyl (1E,4E)-8-bromo-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate, propyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (1.5 equiv), tetrakis(triphenylphosphine)palladium(0), 2M aqueous potassium carbonate (3 equiv) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) afforded propyl 2-(4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:5]2=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].ClC1C=CC=C(C(OO)=[O:26])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[N+:7]([O-:26])=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:5]2=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1cc2c(nc1C)CCCCC2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cc2c([n+]([O-])c1C)CCCCC2
Reaction time: 2 h
Yield: 74.8 %

Procedure:
In an atmosphere of argon, ethyl 2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (13.50 g, 57.9 mmol) was dissolved in methylene chloride (300.0 ml) to which was subsequently added metachloroperbenzoic acid (87.9%, 14.79 g, 75.3 mmol) in small portions at 0° C., and the resulting mixture was stirred at the same temperature for 2 hours and then at room temperature for 10 hours. The reaction solution was mixed with saturated sodium bicarbonate aqueous solution at 0° C. and extracted with methylene chloride, and the thus obtained organic layer was washed with saturated sodium bicarbonate aqueous solution, water and saturated brine in that order and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (ethyl acetate:hexane=5:1—ethyl acetate) to obtain the title compound (10.80 g, 74.9%) as white powder.
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]([CH2:10][C:11]3[CH:30]=[CH:29][C:14]4[N:15]=[C:16]([N:18]5[C@@H:22]6[CH2:23][CH2:24][CH2:25][CH2:26][C@H:21]6[O:20]C5(C)C)[S:17][C:13]=4[CH:12]=3)[CH:6]=[N:7]2)=[N:3][CH:2]=1.C(Cl)Cl>C(O)(C(F)(F)F)=O>[N:1]1[CH:9]=[C:8]2[C:4]([N:5]([CH2:10][C:11]3[CH:30]=[CH:29][C:14]4[N:15]=[C:16]([NH:18][C@@H:22]5[CH2:23][CH2:24][CH2:25][CH2:26][C@H:21]5[OH:20])[S:17][C:13]=4[CH:12]=3)[CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(Cn3cnc4cncnc43)cc2s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cncnc43)cc2s1
Yield: 3.7 %

Procedure:
A solution of (3aR,7aR)-3-(6-((9H-purin-9-yl)methyl)benzo[d]thiazol-2-yl)-2,2-dimethyloctahydrobenzo[d]oxazole (220 mg, 0.5 mmol) from Step 7 of this Example in TFA (5 mL) and CH2Cl2 (5 mL) was stirred for 2 h at rt. The mixture was concentrated under reduced pressure and the residue was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1R,2R)-2-((6-((9H-purin-9-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (7 mg, 4%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.96 (s, 1H), 8.74 (s, 1H), 8.01 (d, J=7.5 Hz, 1H), 7.68 (d, J=1.1 Hz, 1H), 7.17-7.36 (m, 2H), 5.50 (s, 2H), 4.78 (d, J=4.5 Hz, 1H), 3.52 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.57-1.67 (m, 2H), 1.11-1.34 (m, 4H). LCMS (ESI) m/z 381 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:19])[C:7]=1[CH:8]([O:11][Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][CH3:14])[CH2:9][NH2:10].[F:20][C:21]([F:28])([F:27])[C:22]([CH3:26])([CH3:25])[CH:23]=O.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:19])[C:7]=1[CH:8]([O:11][Si:12]([CH2:15][CH3:16])([CH2:17][CH3:18])[CH2:13][CH3:14])[CH2:9][NH:10][CH2:23][C:22]([CH3:26])([CH3:25])[C:21]([F:28])([F:27])[F:20]
Reactant: CC[Si](CC)(CC)OC(CN)c1c(Cl)cncc1Cl
Reactant: CC(C)(C=O)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC[Si](CC)(CC)OC(CNCC(C)(C)C(F)(F)F)c1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
To a yellow clear mixture of 2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethanamine (3.57 g, 11.11 mmol) in DCM (37.0 mL) was added 3,3,3-trifluoro-2,2-dimethylpropanal (11.11 mmol) in DCM followed by AcOH (0.770 ml, 13.33 mmol) and NaBH(OAc)3 (3.53 g, 16.67 mmol). The yellow heterogeneous mixture was stirred at room temperature. After 8 h, the mixture was quenched with saturated NaHCO3 (100 mL). The reaction mixture was extracted with DCM (2×100 mL). The organic extract was dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as orange syrup. The crude material was absorbed onto a plug of silica gel and purified by silica gel column chromatography eluting with a gradient of 0% to 20% EtOAc in heptane to provide N-(2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)-3,3,3-trifluoro-2,2-dim ethylpropan-1-amine (A294) (3.4393 g, 7.72 mmol, 69.5% yield) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.44 (2H, s), 5.48 (1H, dd, J=7.7, 4.4 Hz), 3.27 (1H, dd, J=12.3, 8.4 Hz), 2.58-2.83 (3H, m), 1.25-1.44 (1H, m), 1.10 (6H, s), 0.85-0.94 (9H, m), 0.47-0.64 (6H, m); LCMS (ESI) m/z 445.1 (M+H)+.
Reaction SMILES: [C:1]([C:9]1[C:10](C(=O)C2C=CC=CC=2)=[N:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([NH2:33])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[C:1]([C:9]1[CH:10]=[N:11][C:12](=[N:33][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[C:13](=[N:33][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[C:14]=1[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc2ccccc12
Reactant: O=C(c1ccccc1)c1cccnc1C(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(C1=C(C(=O)c2ccccc2)C(=Nc2cccc3ccccc23)C(=Nc2cccc3ccccc23)N=C1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TiCl4 (0.4 ml, 3.5 mmol) in toluene (20 ml) was added to a mixture of dibenzoylpyridine (0.91 g, 3.2 mmol) and 1-naphthylamine (2.90 g, 17 mmol) in toluene (50 ml) at 0° C. After the addition was complete, the reaction was stirred at room temperature for 1 hour and then under refluxed for 3 hours. The solid was filtered and washed with toluene. The solvent was removed under vacuum. The ligand was isolated after the column chromatography (hexane/ethyl acetate=5/1) to produce a yield of 0.65 g.
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH2:8][CH2:9][C:10](=[O:13])[CH2:11][CH2:12][C:6]=2[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[N+:21]([O-])([O-:23])=[O:22].[K+].[Br-]>C(Cl)Cl>[Br:1][C:2]1[C:7]2[CH2:8][CH2:9][C:10](=[O:13])[CH2:11][CH2:12][C:6]=2[C:5]([O:14][CH3:15])=[C:4]([N+:21]([O-:23])=[O:22])[CH:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccc(Br)c2c1CCC(=O)CC2
Agent: O=S(=O)(O)O
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: COc1c([N+](=O)[O-])cc(Br)c2c1CCC(=O)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77.1 %

Procedure:
To a stirred solution of 1-bromo-4-methoxy-5,6,8,9-tetrahydro-benzocyclohepten-7-one (20.0 g, 0.0743 mol) in sulfuric acid (200 mL, 4 mol) at 0° C. under an atmosphere of nitrogen was added potassium nitrate (7.89 g, 0.0780 mol) in portions. Note: When excess potassium nitrate is added, ipso substitution of the bromide is observed. After stirring for ˜15 min., an aliquot was removed and analyzed by HPLC indicating the completion of the reaction. Mixture was poured over ice water. A gummy solid formed which was dissolved in methylene chloride. The reaction mixture was transferred to a separatory funnel and the water layer removed. The organic phase was washed with saturated aqueous bicarbonate and water, dried over magnesium sulfate, filtered and concentrated in vacuo to an orange solid. Product was purified by ISCO chromatography on silica gel (350 g column) using ethyl acetate-hexane (10-100%). Fractions corresponding to product were combined and concentrated in vacuo to give 4-Bromo-1-Methoxy-2-nitro-5,6,8,9-tetrahydrobenzocyclohepten-7-one (18 g, 77%) as an orange solid. 1H NMR (CDCl3, 400 MHz) 8.04 (s, 1H), 3.90 (s, 3H), 3.25 (m, 2H), 3.15 (m, 2H), 2.64 (m, 4H).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[N:12]1([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>CC(=O)OCC>[N:19]1[CH:20]=[CH:21][CH:22]=[N:23][C:18]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:14][CH2:13]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: ClCc1nc2cccnc2s1
Solvent: CCOC(C)=O
Product: c1cnc(N2CCN(Cc3nc4cccnc4s3)CC2)nc1

Procedure:
The product from Example 38A (150 mg, 0.81 mmol), 2-(1-piperazinyl)pyrimidine (160 mg, 0.98 mmol), and D1 EA (280 μL, 1.6 mmol were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.65 (m, 4H) 3.80 (m, 4H) 4.04 (s, 2H) 6.63 (t, J=4.92 Hz, 1H) 7.56 (dd, J=8.14, 4.75 Hz, 1H) 8.34 (m, 2H) 8.43 (d, J=4.75 Hz, 1H) 8.59 (dd, J=4.75, 1.70 Hz, 1H); (ESI) m/z 313 (M+H)+.