Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([CH2:13][C:14](Cl)=[N:15][OH:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.O1CCCC1.[C:25]([C:27]1[C:28]([NH2:34])=[N:29][C:30]([NH2:33])=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([CH2:13][C:14]3[CH:26]=[C:25]([C:27]4[C:28]([NH2:34])=[N:29][C:30]([NH2:33])=[CH:31][CH:32]=4)[O:16][N:15]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(Oc2ccc(F)cc2)nc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(Oc4ccc(F)cc4)nc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 38.4 %

Procedure:
To a mixture of (6-(4-fluoro-phenoxy)-pyridin-3-yl)-acetohydroximoyl chloride (25 mg) described in Manufacturing Example 75-1-4 and tetrahydrofuran (1 mL) were added 3-ethynyl-pyridin-2,6-diamine (8 mg, 0.060 mmol) described in Manufacturing Example 13-1-3 and triethylamine (17 μL, 0.12 mmol), which was stirred for 5 hours at room temperature. Water was added to the reaction mixture at the same temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (8.7 mg, 38%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2([C:13]([NH2:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:17][C:18]1[N:19]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=2)[CH:20]=[CH:21][N:22]=1>>[CH3:17][C:18]1[N:19]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][O:1][C:2]3[CH:3]=[C:4]([C:8]4([C:13]([NH2:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]4)[CH:5]=[CH:6][CH:7]=3)=[CH:25][CH:24]=2)[CH:20]=[CH:21][N:22]=1
Reactant: Cc1nccn1-c1ccc(CCl)cc1
Reactant: NC(=O)C1(c2cccc(O)c2)CCCC1
Agent: Cl
Product: Cc1nccn1-c1ccc(COc2cccc(C3(C(N)=O)CCCC3)c2)cc1

Procedure:
1-(3-Hydroxyphenyl)cyclopentane-1-carboxamide was reacted with 4-(2-methyl-imidazol-1-yl)benzyl chloride hydrochloride according to the procedure described in Example 2H to give the titled compound. mp: 163.0-164.0° C.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[OH:18])[CH:14]([C:19]([OH:21])=[O:20])[CH2:13][CH2:12]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:27](O)[CH3:28]>>[CH2:27]([O:20][C:19]([CH:14]1[C:15]2[C:11](=[CH:10][C:9]([C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:17]([OH:18])[CH:16]=2)[CH2:12][CH2:13]1)=[O:21])[CH3:28]
Reactant: O=C(c1ccccc1)c1cc2c(cc1O)C(C(=O)O)CC2
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCc2cc(C(=O)c3ccccc3)c(O)cc21

Procedure:
Analogously to Example 3, 12 g of 5-benzoyl-6-hydroxyindane-1-carboxylic acid and ethanol containing sulphuric acid give 5-benzoyl-6-hydroxy-indane-1-carboxylic acid ethyl ester in the form of yellow platelets of melting point 83-4° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][C:16]([S@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17].O>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[C:11](/[CH:12]=[N:21]/[S@@:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc2cc(/C=N/[S@](=O)C(C)(C)C)c(Cl)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
To a solution of 2-chloro-8-methylquinoline-3-carboxaldehyde (2.05 g, 10 mmol) in dry THF (20 mL) under nitrogen was added titanium isopropoxide (5.68 g, 20 mmol) and the mixture stirred at r.t. for 10 minutes. (R)-(+)-2-Methyl-2-propanesulfinamide (1.21 g, 10 mmol) was added to the reaction which was stirred at r.t. for 72 h. Water (20 mL) was added and the mixture was extracted with DCM (150 mL). The organic layer was separated, dried (MgSO4), filtered and the solvent removed in vacuo to afford the title compound (2.4 g, 72%) as a pale yellow solid. δH (CDCl3) 9.12 (s, 1H), 8.79 (s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.67 (d, J=6.8 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 2.79 (s, 3H), 1.32 (s, 9H). LCMS (ES+) 309, 311 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=3)=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=3)=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:31]([F:34])([F:32])[F:33]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccnc(C)c1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)ccn1

Procedure:
A mixture of 4-Chloro-N-[5-chloro-2-(2-methyl-pyridine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (150 mg, 0.27 mmol) from Example 39 dissolved in 4 M HCl in dioxane (10 mL), and water (4 mL) was heated at 100° C. for 3 h. The reaction mixture was concentrated to dryness under reduced pressure and it was treated with aqueous NaHCO3 to adjust pH to 5-6 and extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH: CH2Cl2: 1:99, then 2:98) to provide the desired product. 1H NMR (400 MHz, CDCl3) δ 10.9 (s, 1 H), 8.64 (d, J=5.2 Hz, 1 H), 8.36 (s, 1 H), 8.18-8.16 (m, 2 H), 7.96 (d, J=8.4 Hz, 1H), 7.62 (d, J=8.4 Hz, 1 H), 7.41-7.38 (m, 2 H), 2.64 (s, 3 H); MS m/z: 490.0 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH:3]1[C:9]1[N:13]2[CH:14]=[C:15](F)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.[NH2:19][C@@H:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@H:23]([OH:30])[CH2:22][CH2:21]1.[H-].[Na+].N>CN(C=O)C.CO.C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH:3]1[C:9]1[N:13]2[CH:14]=[C:15]([O:30][C@H:23]3[C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@@H:20]([NH2:19])[CH2:21][CH2:22]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CN1CCN(C)C(c2nnc3ccc(F)cn23)C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCN(C)C(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 66.2 %

Procedure:
To a solution of Intermediate 86c (100 mg, 0.40 mmol) and Intermediate A (79 mg, 0.40 mmol) in DMF (3 mL) was added NaH (60% in mineral oil, 56 mg, 1.4 mmol) portion-wise. The mixture was stirred at 60° C. for 1.5 h then allowed to cool to RT. The mixture was carefully quenched by pouring into MeOH (10 mL) then applied to an SCX-2 cartridge and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-20% [2M NH3 in MeOH] in DCM, gave the title compound as a brown oil (104 mg, 66%). LCMS (Method 4): Rt 0.26, m/z 393 [MH+].
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.I.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](SC)=[NH:26]>CCO.C([O-])([O-])=O.[Na+].[Na+]>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][N:8]1[C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([NH:1][C:25]([C:21]3[S:20][CH:24]=[CH:23][CH:22]=3)=[NH:26])[C:7]1=2
Reactant: CSC(=N)c1cccs1
Reactant: CN(C)CCN1C(=O)CCCc2cccc(N)c21
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)CCN1C(=O)CCCc2cccc(NC(=N)c3cccs3)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 9-amino-1-(2-(dimethylamino)ethyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (85 mg, 0.344 mmol) in EtOH (6 mL) was added methyl thiophene-2-carbimidothioate hydroiodide (196 mg, 0.687 mmol). The resulting suspension was stirred overnight at room temperature. The reaction mixture was then diluted with Na2CO3 (aq, sat) and extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then chromatographed in 2-5% 2M NH3/MeOH in dichloromethane, giving the desired product. Yield: 87 mg, 71%. 1H NMR (DMSO-d6) δ 7.75 (d, 1H, J=3.3 Hz, 7.61 (d, 1H, J=4.5 Hz), 7.16 (d, 1H, J=7.8 Hz), 7.10 (m, 1H), 6.82 (s, 1H), 6.66 (d, 1H, J=8.1 Hz), 6.46 (brs, 2H), 2.65 (m, 3H), 2.28 (m, 3H), 2.17 (m, 2H), 1.9-2.15 (m, 8H). ESI-MS (m/z, %): 357 (MH+, 100), 312 (48), 156 (38), 148 (31).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[Cl:10][CH2:11][CH2:12][CH2:13]I.O>CN(C)C=O.[Na+].[Cl-]>[Cl:10][CH2:11][CH2:12][CH2:13][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:11][CH:12]([NH:4][CH2:3][CH2:2][CH2:7][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH3:13]
Reactant: Oc1cccnc1
Reactant: ClCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NCCCOc1cccnc1
Product: ClCCCOc1cccnc1
Temperature: 25 °C
Yield: 122762.5 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-hydroxypyridine (35.00 g, 0.368 mmol) in N,N-dimethylformamide (DMF) (150 mL) was slowly added drop-wise over 15 min to a cold (0-5° C.), stirring slurry of sodium hydride (17.64 g of an 80% dispersion in mineral oil, 0.588 mol) in DMF (250 mL). The mixture was allowed to stir and warm to ambient temperature over 1 h. The gray slurry was cooled to 0-5° C., and 1-chloro-3-iodopropane (90.3 g, 0.442 mol) was added drop-wise over 30 min. The resulting dark-brown mixture was allowed to stir and warm to ambient temperature over 16 h. Water (500 mL) was added and the mixture was divided into equal parts. Each half was diluted with saturated NaCl solution (200 mL) and extracted with ether (5×200 mL). All ether extracts were combined and concentrated to give 55.1 g (87.3%) of a dark-brown oil.
Reaction SMILES: [O:1]=[S:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[NH:14][C:15](=O)[C:16]3[S:21][C:20]([CH3:22])=[CH:19][C:17]=3[N:18]=2)[CH2:4][CH2:3]1.[CH2:24]([NH2:27])[CH2:25][NH2:26]>>[CH3:22][C:20]1[S:21][C:16]2[C:15]([NH:26][CH2:25][CH2:24][NH2:27])=[N:14][C:13]([N:5]3[CH2:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[S:2](=[O:1])[CH2:3][CH2:4]3)=[N:18][C:17]=2[CH:19]=1
Reactant: Cc1cc2nc(N3CCS(=O)c4ccccc4C3)[nH]c(=O)c2s1
Reactant: NCCN
Product: Cc1cc2nc(N3CCS(=O)c4ccccc4C3)nc(NCCN)c2s1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 3 by using 2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylthieno[3,2-d]pyrimidin-4(3H)-one and ethylenediamine. MS obsd. (ESI+) [(M+H)+] 388, 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.68-7.75 (m, 2H), 7.41-7.51 (m, 2H), 6.81 (s, 1H), 5.21 (d, J=5.6 Hz, 1H), 4.65-4.81 (m, 2H), 4.48 (br. s., 1H), 3.68 (m, 2H), 3.32-3.47 (m, 2H), 2.50 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[C:5]([OH:11])=[CH:4][C:3]=1[OH:12].[CH2:13]1N2CN3CN(C2)CN1C3.[OH2:23]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:3]([OH:12])=[C:4]([C:5]([OH:11])=[C:6]([CH2:8][CH2:9][CH3:10])[CH:7]=1)[CH:13]=[O:23]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O
Reactant: CCCc1cc(Cl)c(O)cc1O
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cc(Cl)c(O)c(C=O)c1O

Procedure:
To a solution of 2-chloro-4-propyl-1,5-dihydroxybenzene (from Step a, 243 mg, 1.3 mmol) in 10 mL trifluoroacetic acid was added 1 g of hexamine. The mixture was refluxed for 20 h. Water was added and the mixture was extracted with ethyl acetate. Chromatography of the concentrated organic extracts gave the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.C(NC(C)C)(C)C.[NH2:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1.O>CN(C=O)C>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([NH:18][C:19]2[NH:20][N:21]=[C:22]([CH3:24])[CH:23]=2)[CH:7]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: Cc1cc(N)n[nH]1
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc(Cl)cc(Nc2cc(C)n[nH]2)n1
Temperature: 50 °C
Yield: 67.5 %

Procedure:
To a stirred solution of 4,6-dichloro-2-(methylthio)pyrimidine (25 g, 0.128 mol) in DMF (100 ml) was added diisopropylamine (19.8 g, 0.154 mol) followed by 3-amino-5-methylpyrazole (13.7 g, 0.154 mol) portionwise over 10 minutes. The solution was heated to 50° C. for 16 hours, after which time all of the starting material had reacted (by LC/MS analysis). The mixture was cooled to ambient and poured into water (250 ml). The precipitate was filtered and the wet solid slurried in diethyl ether (300 ml). The solid was again filtered and re-slurried in methanol (100 ml). The filtered product was air dried on the sinter, then further dried under vacuum. This afford the title compound as an off-white solid (22.1 g, 66% yield). 1H NMR (d6-DMSO) δ 2.22 (3H, s, CH3), 3.31 (3H, s, CH3), 6.00-7.50 (2H, br, CH), 10.17 (1H, s, NH), 12.10 (1H, s, NH); MS ES+ 256.08, ES− 254.25.
Reaction SMILES: [H-].[Na+].CS(C)=O.[Br-].[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[C:37]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)(=O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O1CCCC1>[C:38]1([C:37]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:8]([OH:10])=[O:9])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(O)CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=C(O)CCCCCCC=C(c1ccccc1)c1ccccc1
Yield: 55.5 %

Procedure:
The reaction was carried out as in Example 87 using the following reagents: sodium hydride (56% dispersion in oil; 8.6 g), dimethylsulfoxide (100 mL), (7-carboxyheptyl)triphenylphosphonium bromide (39.95 g), benzophenone (18.2 g), and tetrahydrofuran (100 mL). The crude acid, isolated in the usual manner, required further purification by HPLC (hexane-ether; 3:2). The appropriate fractions were combined and evaporated and the residue was crystallized from hexane to provide 14.1 g of 9,9-diphenyl-8-nonenoic acid, mp 77.5°-78.5° C. Anal. Calculated for C21H24O2 : C, 81.78; H, 7.84. Found: C, 81.71; H, 7.70.
Reaction SMILES: Cl.C[O:3][C:4](=[O:8])[CH:5]([CH3:7])[NH2:6].[C:9](Cl)(=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[C:9]([NH:6][CH:5]([CH3:7])[C:4]([OH:3])=[O:8])(=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: COC(=O)C(C)N
Agent: Cl
Product: CCCCCCCCCC(=O)NC(C)C(=O)O

Procedure:
The preparation is carried out analogously to the procedure of example 4A using 19.0 g (184 mmol) of D,L-alanine methyl ester hydrochloride and 35.14 g (184 mmol) of decanoyl chloride.
Reaction SMILES: [C@H:1]12[NH:8][C@H:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH:2]2[C:9]([O:11][CH3:12])=[O:10].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Br.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][N:8]1[C@@H:5]2[CH2:6][CH2:7][C@H:1]1[CH:2]([C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:4]2
Reactant: Fc1ccccc1CBr
Reactant: COC(=O)C1CC[C@H]2CC[C@@H]1N2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CC[C@H]2CC[C@@H]1N2Cc1ccccc1F
Reaction time: 1 h
Yield: 61 %

Procedure:
To (1S,5S)-methyl 8-azabicyclo[3.2.1]octane-2-carboxylate (185 mg, 1.1 mmol) dissolved in DCM (11 mL) was added 2-fluorobenzylbromide (206 mg, 1.1 mmol), followed by N,N-diisopropylethylamine (424 mg, 3.3 mmol). After stirring for 1 hour, the reaction mixture was quenched with water, and extracted with DCM. Dried and concentrated to give 186 mg of crude product. The crude was carried over the next step without further purification.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([CH2:23][O:24][CH3:25])[O:17]2)=[C:9]([NH:26][CH2:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]=1)(=O)=O.[CH3:41][C:42]1[C:47]([NH2:48])=[CH:46][CH:45]=[C:44]([CH3:49])[N:43]=1.C(N(CC)CC)C>C(OCC)(=O)C.CN(C)C=O>[CH3:41][C:42]1[C:47]([NH:48][CH2:6][C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@H:16]3[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([CH2:23][O:24][CH3:25])[O:17]3)=[C:9]([NH:26][CH2:27][CH:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:8]=2)=[CH:46][CH:45]=[C:44]([CH3:49])[N:43]=1
Reactant: Cc1ccc(N)c(C)n1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COS(C)(=O)=O)nc32)[C@H](O)[C@@H]1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNc4ccc(C)nc4C)nc32)[C@H](O)[C@@H]1O
Temperature: 60 °C
Reaction time: 24 h
Yield: 11.6 %

Procedure:
{9-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl methanesulfonate (preparation 25) (75 mg, 0.13 mmol) was added to a solution of 2,6dimethyl-3-pyridinylamine (22 mg, 0.17 mmol) and triethylamine (0.036 ml, 0.26 mmol) in ethyl acetate (3 ml) and N,N-dimethylformamide (1 ml) in the reaction vessel of a Argonaut Quest 210 machine. The reaction mixture was agitated and heated to 60° C. for 12 hr. More 2,6-dimethyl-3-pyridinylamine (22 mg, 0.17 mmol) and triethylamine (0.036 ml, 0.26 mmol) were added and heating and agitation continued for a further 24 hr. The reaction mixture was then washed with water and the organic phase separated and dried with anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give a residue which was purified by reverse phase HPLC using firstly a Lana C8 (2) column and then a Magellan C18 column eluting with 5 mM ammonium acetate in water:2 mM ammonium acetate in acetonitrile (90:10) decreasing in polarity to 5 mM ammonium acetate in water:2 mM ammonium acetate in acetonitrile (10:90) as eluant. This gave the title compound (9 mg) as a gum. MS: 596 (MH+).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>C1(C)C=CC=CC=1>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1

Procedure:
To a cooled (5-10° C.) mixture of N-Boc-4-hydroxypiperidine (25.0 g, 124 mmol) and triethylamine (19.6 ml, 136 mmol) in toluene (120 ml) was added slowly methanesulfonyl chloride (10.6 ml, 136 mmol) via a syringe. The rate of the addition was kept at such rate that the temperature of the reaction mixture did not rise above 20° C. After completion of the addition, the temperature was kept at room temperature for one and a half hours. Water (50 ml) was added to the mixture, and an emulsion formed that was broken by the addition of 100 ml toluene. The aqueous layer was extracted with 100 ml toluene and the combined organic layers were dried over sodium sulfate, filtered, and evaporated to dryness, leaving a white solid residue identified as the product (30.5 g, 87%), and which was used as such in the next step.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C@H:12]([NH2:14])[CH3:13])=[CH:9][CH:10]=2)[CH:5]=[N:4]1.[F:15][C:16]([F:34])([F:33])[C:17]([C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][C@@H:25]([C:30](O)=[O:31])[CH2:24][CH2:23][C:22]=2[N:21]=1)([CH3:19])[CH3:18].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>CN1C(=O)CCC1>[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C@H:12]([NH:14][C:30]([CH:25]3[CH2:24][CH2:23][C:22]4[N:21]=[C:20]([C:17]([CH3:19])([CH3:18])[C:16]([F:34])([F:33])[F:15])[CH:29]=[CH:28][C:27]=4[CH2:26]3)=[O:31])[CH3:13])=[CH:9][CH:10]=2)[CH:5]=[N:4]1
Reactant: C[C@@H](N)c1ccc2[nH]ncc2c1
Reactant: CC(C)(c1ccc2c(n1)CC[C@H](C(=O)O)C2)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)C1CCc2nc(C(C)(C)C(F)(F)F)ccc2C1)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
A 2 mL vial was charged sequentially with a solution of (R)-1-(1H-indazol-5-yl)ethanamine dihydrochloride (34 mg, 0.15 mmol) in NMP (0.2 mL), a solution of (S)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (38 mg, 0.13 mmol) and N,N-diisopropylethylamine (93 μL, 0.53 mmol) in NMP (0.1 mL). A solution of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (61 mg, 0.16 mmol) in NMP (0.3 mL) was added to the resulting mixture and the solution stirred at room temperature. After 30 min the mixture was filtered and purified by reverse-phase HPLC (20-75% MeCN in 10 mM Et2NH/H2O) to afford the amide as a solid (41 mg, 71%). 1H NMR (400 MHz, DMSO-d6) δ 12.99 (br s, 1H), 8.42 (d, J=8.0 Hz, 1H), 8.04 (s, 1H), 7.66 (s, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.50 (d, J=8.6 Hz, 1H), 7.38-7.32 (m, 2H), 5.05 (app pentet, J=7.0 Hz, 1H), 2.96-2.78 (m, 4H), 2.68-2.60 (m, 1H), 2.05-1.97 (m, 1H), 1.82-1.69 (m, 1H), 1.53 (s, 6H), 1.42 (d, J=7.0 Hz, 3H); m/z=431.2 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C@@H:18]3[CH:23]4[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]4)[CH2:19]3)=[O:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:26][N:27]=[C:28]=[O:29]>C1COCC1.CN(C=O)C>[CH3:26][NH:27][C:28](=[O:29])[O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C@@H:18]3[CH:23]4[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]4)[CH2:19]3)=[O:17])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: O=C(Nc1ccc(-c2ccc(CO)cc2)cc1)[C@H]1CN2CCC1CC2
Reactant: CN=C=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)OCc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
35 mg (0.10 mmol) of (3R)-N-[4′-(hydroxymethyl)-1,1′-biphenyl-4-yl]-1-azabicyclo-[2.2.2]octane-3-carboxamide are dissolved in 1 ml of a 1:1 THF/DMF mixture. 12 mg (0.21 mmol) of methyl isocyanate are added, and the mixture is stirred at 60° C. overnight. The solvent is removed under reduced pressure, and the crude product is purified by preparative HPLC. 20 mg (49% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][C:3]=1[OH:10].Br[CH2:12][CH:13]1[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][C:3]=1[O:10][CH2:12][CH:13]1[CH2:15][CH2:14]1
Reactant: Cc1cc(Br)c(O)cc1F
Reactant: BrCC1CC1
Product: Cc1cc(Br)c(OCC2CC2)cc1F

Procedure:
Starting from 2-bromo-5-fluoro-4-methyl-phenol (example B.a3) and commercially available bromomethyl-cyclopropane the title compound is obtained as colorless oil after distillation at 5×10−3 mbar.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(#N)C>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:3][C:4]2[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=2)[O:7][CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:25][CH2:24]1
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CC#N
Product: CN1CCN(Cc2cccc(OCc3ccc4ccccc4n3)c2)CC1
Yield: 11.5 %

Procedure:
A mixture of 4.7 g (0.015 mol) 2-(3-chloromethylphenoxymethyl) quinoline hydrochloride, 6 g (0.06 mol) N-methylpiperazine in 50 ml acetonitrile was heated over steam bath for a period of 8 hours. Reaction mixture was concentrated to dryness and sluried into water, and extracted with ether. The ether extract was washed with water, dried over MgSO4 and concentrated to dryness under reduced pressure. The residue was passed through a silica gel column using acetone as eluent. Evaporation of eluent gave solid (0.6 g), m.p. 47°-49° C.