Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:41]1([C:45]2[O:49][N:48]=[C:47]([CH2:50][O:51][C:52]3[C:57]([CH3:58])=[CH:56][CH:55]=[CH:54][C:53]=3[CH3:59])[C:46]=2[CH2:60]O)[CH2:44][CH2:43][CH2:42]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH:41]1([C:45]2[O:49][N:48]=[C:47]([CH2:50][O:51][C:52]3[C:53]([CH3:59])=[CH:54][CH:55]=[CH:56][C:57]=3[CH3:58])[C:46]=2[CH2:60][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:17]=[C:16]4[C:11]([CH:12]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[N:14]=[CH:15]4)=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH2:42][CH2:43][CH2:44]1
Reactant: Cc1cccc(C)c1OCc1noc(C2CCC2)c1CO
Reactant: COC(=O)c1cc2ccc(-c3ccc(O)cc3)cc2cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc2ccc(-c3ccc(OCc4c(COc5c(C)cccc5C)noc4C4CCC4)cc3)cc2cn1
Temperature: 90 °C
Yield: 58.7 %

Procedure:
To a solution of methyl 7-(4-hydroxyphenyl)-3-isoquinolinecarboxylate (90 mg, 0.32 mmol), triphenylphosphine (93 mg, 0.35 mmol), and (5-cyclobutyl-3-{[(2,6-dimethyl phenyl)oxy]methyl}-4-isoxazolyl)methanol (93 mg, 0.32 mmol) in dichloromethane (1.5 mL) was added diisopropyl azodicarboxylate (0.064 mL, 0.35 mmol) dropwise. The solution was heated in a microwave reactor at 90° C. for 10 minutes. The solution was concentrated, adsorbed onto silica gel and purified by chromatography (silica gel, 0-25% acetone in hexanes gradient elution) to afford methyl 7-(4-{[(5-cyclobutyl-3-{[(2,6-dimethylphenyl)oxy]methyl}-4-isoxazolyl)methyl]oxy}phenyl)-3-isoquinolinecarboxylate (103 mg, 58%). 1H-NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.64 (s, 1H), 8.50 (s, 1H), 8.26-8.19 (m, 2H), 7.85 (d, J=9 Hz, 2H), 7.16 (d, J=9 Hz, 2H), 7.00-6.90 (m, 3H), 5.06 (s, 2H), 4.90 (s, 2H), 3.99-3.90 (m, 1H), 3.91 (s, 3H), 2.37-2.30 (m, 4H), 2.14 (s, 6H), 2.09-2.01 (m, 1H), 1.98-1.89 (m, 1H).
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[H-].[Na+].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>C1COCC1>[I:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=1
Reactant: CCOC(=O)CBr
Reactant: Ic1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1cnc(I)c1
Reaction time: 0.33 h
Yield: 67.5 %

Procedure:
To a solution of 4-iodoimidazole (1.93 g, 9.95 mmol) in dry THF (50 mL) at 0° C. was added sodium hydride (60% dispersion, 0.43 g, 10.8 mmol) and the mixture was stirred for 20 min. Ethyl bromoacetate (1.1 mL, 1.7 g, 10 mmol) was added by syringe and the cloudy mixture was stirred for 15 min. It was then partitioned between ethyl acetate and water. The organic phase was collected, washed with brine, dried (anhydrous MgSO4), filtered, and concentrated. Silica gel chromatography (50%->75% ethyl acetate/hexanes) of the residue provided 372 (1.88 g, 67% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.57 (d, J=1.4, 1H); 7.32 (d, J=1.4, 1H); 4.93 (s, 2H); 4.13 (q, J=8.0, 2H); 1.20 (t, J=7.2, 3H). LRMS (M+H): 281.0.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([N:17]([CH3:30])[CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[C:13](=[O:31])[CH2:12]1)=O)C1C=CC=CC=1.[ClH:32]>C(OCC)(=O)C.CO.[Pd]>[ClH:32].[ClH:32].[CH3:30][N:17]([CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)[N:14]1[CH2:15][CH2:16][NH:11][CH2:12][C:13]1=[O:31]
Reactant: CN(C1CCN(c2ccncc2)CC1)N1CCN(C(=O)OCc2ccccc2)CC1=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C1CCN(c2ccncc2)CC1)N1CCNCC1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 4-benzyloxycarbonyl-1-{methyl[1-(4-pyridyl)-4-piperidinyl]amino}-2-piperazinone (2.22 g) and a 4N solution of hydrochloric acid in ethyl acetate (2.6 ml) in methanol (50 ml) was combined with 10% Pd/C (50% hydrated, 0.44 g) and stirred at room temperature for 5 hours under a hydrogen atmosphere. The catalyst was filtered off and the reaction mixture was concentrated to obtain the title compound. (2.13 g) as a yellow amorphous material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:20]2[CH:21]=[CH:22][NH:23][C:19]=2[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[NH:23][CH:22]=[CH:21][C:20]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2[nH]ccc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2cc[nH]c2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: Cl.Cl.[CH2:3]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)[CH2:4][CH2:5][CH3:6].[BrH:21]>C(O)(=O)C>[BrH:21].[CH2:3]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)[CH2:9][CH2:8]1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCN1CCN(c2ccc(OC)cc2)CC1
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Product: CCCCN1CCN(c2ccc(O)cc2)CC1
Yield: 81 %

Procedure:
A mixture of 12.5 parts of 1-butyl-4-(4-methoxyphenyl)piperazine dihydrochloride and 150 parts of hydrobromic acid solution 48% in glacial acetic acid is stirred and refluxed overnight. The reaction mixture is evaporated and the residue is triturated in 2-propanone. The product is filtered off and crystallized from water, yielding 13.1 parts (81%) of 4-(4-butyl-1-piperazinyl)phenol monohydrobromide; mp. 281.9° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]2[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]2)=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[C:9]32[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[NH:23][C:22]3=[O:31])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:16]=[C:17]([Cl:21])[CH:18]=[CH:19][CH:20]=3)[C:9]32[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[NH:23][C:22]3=[O:31])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2C2CC(=O)NC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cc(Br)ccc2OC2CCNCC2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cccc(Cl)c2)N1
Yield: 97.5 %

Procedure:
In a manner similar to the method described in Example 38a, racemic (2′S,3S,4′R)-4′-[5-bromo-2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-phenyl]-6-chloro-2′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.75 g, 1 mmol) was reacted with trifluoroacetic acid in dichloromethane to give title compound as a yellow solid (Yield: 0.6 g, 93%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:20][C:21]4[N:22]([C:24]([C:27]5[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=5)=[CH:25][N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl>O1CCOCC1>[CH3:36][S:33]([C:30]1[CH:31]=[CH:32][C:27]([C:24]2[N:22]3[N:23]=[C:18]([C:15]4[CH:14]=[CH:13][C:12]([C:8]5([NH2:7])[CH2:11][CH2:10][CH2:9]5)=[CH:17][CH:16]=4)[C:19]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:20][C:21]3=[N:26][CH:25]=2)=[CH:28][CH:29]=1)(=[O:35])=[O:34]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nn4c(-c5ccc(S(C)(=O)=O)cc5)cnc4cc3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2cnc3cc(-c4ccccc4)c(-c4ccc(C5(N)CCC5)cc4)nn23)cc1
Reaction time: 2 h
Yield: 21 %

Procedure:
120 mg (0.2 mmol) (1-{4-[3-(4-Methanesulfonyl-phenyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamic acid tert.-butyl ester, intermediate example Int-3-2, were stirred with 10 mL 4M hydrogen chloride in dioxane for 23 hours at room temperature. The solvent was evaporated and the residue was treated with saturated sodium bicarbonate solution (pH 9). After stirring for two hours 100 mL dichloromethane were added and stirring was continued for one hour. The organic phase was separated and the aqueous phase was extracted once more with dichloromethane (50 mL). The combined organic extracts were washed with water, brine, dried, filtrated and the solvent was evaporated. The crude product (97.8 mg) was purified by HPLC to yield 20.8 mg of the title compound.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.[OH:19][C:20]([CH3:32])([C:26]#[C:27][Si](C)(C)C)[C:21]([O:23][CH2:24][CH3:25])=[O:22].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(=O)(O)[O-].[Na+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:27]#[C:26][C:20]([OH:19])([CH3:32])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:10]=3)[C:6]([CH3:18])=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: Cc1nn(-c2ccnc(N)n2)c2cc(I)ccc12
Reactant: CCOC(=O)C(C)(O)C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(O)C#Cc1ccc2c(C)nn(-c3ccnc(N)n3)c2c1
Temperature: 50 °C

Procedure:
To a solution of 4-(6-iodo-3-methyl-1H-indazol-1-yl)pyrimidin-2-amine (170 mg, 0.38 mmol) in dry THF (3 mL) was introduced bis(triphenylphosphine)palladium(II) chloride (27 mg, 0.04 mmol), ethyl 2-hydroxy-2-methyl-4-(trimethylsilyl)but-3-ynoate (164 mg, 0.76 mmol) and TBAF (0.46 mL of a 1M solution in THF, 0.46 mmol). The solution was warmed to 50° C. for 1.5 hr. After cooling, sodium bicarbonate (4 mL of saturated aqueous NaHCO3) was introduced and the solution extracted with EtOAc (3×10 mL extractions). The combined organic extracts were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by silica gel flash column chromatography (DCM containing a 1-10% gradient of methanol) furnished the title compound as an orange oil: 1H NMR (250 MHz, Chloroform-d) delta 1.39 (3H, t, J=7.1 Hz), 1.83 (3 H, s), 2.60 (3H, s), 4.38 (2H, q, J=7.1 Hz), 5.20 (2H, s), 7.29 (1H, s), 7.34 (1H, dd, J=8.2, 1.3 Hz), 7.60 (1H, dd, J=8.2, 0.7 Hz), 8.29 (1H, d, J=5.7 Hz), 8.83 (1H, s); LC-MS: m/z=+366.05 (M+H)+.
Reaction SMILES: O=S(Cl)[Cl:3].[C:5]([OH:17])(=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15]>C1(C)C=CC=CC=1>[C:5]([Cl:3])(=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15]
Reactant: C=CCCCCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: C=CCCCCCCCCC(=O)Cl

Procedure:
A mixture of toluene (12 mL) and SOCl2 (7.75 g, 65 mmol) and undec-10-enoic acid (1.00 g, 5.43 mmol) were refluxed for 1.5 h. The solvent and remaining SOCl2 were distilled off and the product (X) was further used in the thioester synthesis. 1H-NMR (CDCl3): δ=5.90-5.74 (m, 1H), 5.06-4.91 (m, 2H), 2.87 (t, J=7.2 Hz, 2H), 2.06 (q, J=13.7 Hz, J=6.7 Hz, 2H), 1.78-1.61 (m, 2H), 1.49-1.23 (m, 8H).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:26])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.[CH2:44]([O:51][C:52]1[CH:59]=[CH:58][C:55]([CH:56]=[O:57])=[CH:54][CH:53]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>ClCCl.C(N(CC)CC)C>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:26])[C@H:15]([O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH3:24])[CH3:25])=[CH:19][CH:18]=1)[C@@H:56]([C:55]1[CH:58]=[CH:59][C:52]([O:51][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:53][CH:54]=1)[OH:57])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(OCC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(O[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)[C@H](O)c2ccc(OCc3ccccc3)cc2)cc1
Yield: 75.6 %

Procedure:
In a similar manner to that described in Reference example 29(b), a reaction was carried out using (R)-4-benzyl-3-[(4isopropylphenoxy)acetyl]oxazolidine-2-one (10.0 g), which is the product of Reference example 30(a), solution of dibutylboron triflate in dichloromethane (1M, 34.0 ml), triethylamine (5.11 ml) and 4-benzyloxybenzaldehyde (6.60 g) and the reaction mixture was treated to afford the desired compound (12.1 g) as a mass of foam.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:28][CH2:29][O:30][CH3:31])[CH2:18][C@@H:19]2[OH:27])=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7].CC1(C)COC(C([C@@H]2[C@]3(C)[C@H](C4[C@H](CC3)[C@]3(C)C(C[C@@H](OC(OC)=O)C[C@@H]3OC(OC)=O)=CC=4)CC2)C)OC1>>[OH:27][C@@H:19]1[C@@:20]2([CH3:21])[C:15](=[CH:14][CH:13]=[C:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:25]2([CH3:26])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[CH:6]([CH:2]=[O:1])[CH3:7])[CH2:16][C@@H:17]([O:28][CH2:29][O:30][CH3:31])[CH2:18]1
Reactant: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](O)C1
Agent: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Product: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](O)C1
Yield: 59 %

Procedure:
The reaction and workup procedures of Example 156 were repeated except that 100 mg of 20-(1,3-dioxolan-2-yl)-3β-(methoxymethyl)oxypregna-5,7-dien-1α-ol was used in lieu of 100 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene to give 53 mg of 1α-hydroxy-3β-(methoxymethyl)oxypregna-5,7-diene-20-carbaldehyde showing the following physical properties.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3([CH2:20][CH2:19]3)[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:23][C:24]1[C:40]([O:41][CH3:42])=[CH:39][C:27]([C:28]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]2)=[O:29])=[C:26]([F:43])[CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>CC(C)CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:20][CH2:19]3)[C:7](=[O:21])[N:6]([CH3:22])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[C:40]([O:41][CH3:42])=[CH:39][C:27]([C:28]([NH:30][CH:31]5[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]5)=[O:29])=[C:26]([F:43])[CH:25]=4)=[N:12][C:11]2=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCN1CCC(NC(=O)c2cc(OC)c(N)cc2F)CC1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Solvent: O
Solvent: CO
Product: CCN1CCC(NC(=O)c2cc(OC)c(Nc3ncc4c(n3)N(C3CCCCC3)CC3(CC3)C(=O)N4C)cc2F)CC1
Temperature: 110 °C
Yield: 48.7 %

Procedure:
2′-chloro-9′-cyclohexyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 270; 54 mg, 0.17 mmol), 4-amino-N-(1-ethyl-4-piperidyl)-2-fluoro-5-methoxy-benzamide (Intermediate 205; 50 mg, 0.17 mmol), and p-toluenesulphonic acid monohydrate (81 mg, 0.43 mmol) were stirred together in 4-methyl-2-pentanol (3 mL) and heated at 110° C. for 18 hours. The cooled reaction mixture was loaded onto an SCX-3 (5 g) column pre-wet with MeOH. The column was washed with MeOH (2 column volumes) and eluted with 2M NH3/MeOH. Solvent evaporation of the combined ammoniacal fractions gave a brown gum which was purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (48 mg, 49%)
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([OH:12])[C:10]#[CH:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].CCCCCC>CN(C)C=O>[C:3]1([CH:9]([O:12][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:10]#[CH:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)CBr
Reactant: C#CC(O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C#CC(OCC(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.5 %

Procedure:
To a stirred suspension of NaH (60%, 76 mg, 1.89 mmol) in 5 mL of anhydrous N,N-dimethylformamide was added 1-phenylprop-2-yn-1-ol (250 mg, 1.89 mmol). After 15 min at room temperature, methyl bromoacetate (179 μL, 1.89 mmol) was added. The resulting mixture was stirred at room temperature for 90 min before it was quenched with saturated ammonium chloride and extracted with ethyl acetate (2×15 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuuo. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate:hexane (1.9), to provide the title compound as a colorless oil (160 mg, 41% yield).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[Br:13]Br.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:13][C:12]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=1
Reactant: CC(C)c1ccc2c(c1)OCO2
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)c1cc2c(cc1Br)OCO2
Temperature: 10 °C
Reaction time: 8.5 h
Yield: 100.6 %

Procedure:
2.94 g of 5-isopropyl-1,3-benzodioxole was dissolved in 30 ml of carbon tetrachloride to obtain a solution. A solution of 3.15 g of bromine in 5 ml of carbon tetrachloride was dropwise added to the solution at a temperature of -5° to 5° C. The obtained mixture was stirred at 10° C. for 8.5 hours. Nitrogen gas was passed through the resulting mixture, followed by the addition of a saturated aqueous solution of sodium hydrogencarbonate and an aqueous solution of sodium thiosulfate. The obtained mixture was extracted with chloroform and the organic layer was washed with a saturated aqueous solution of common salt, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain 4.38 g of the title compound as a crude oil.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4]1.[Li].C([BH-](C(CC)C)C(CC)C)(CC)C.Cl>C1(C)C=CC=CC=1.CCCCCC.O1CCCC1>[CH3:1][NH:2][CH:3]1[CH2:9][CH:8]([OH:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4]1
Reactant: CNC1COc2ccccc2C(=O)C1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: Cl
Agent: [Li]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CNC1COc2ccccc2C(O)C1

Procedure:
To a boiling solution of 80 g (0.5 mole) rac.-3-methylamino-3,4-dihydro-1-benzoxepin-5-(2H)-one in a mixture of 550 ml toluene and 300 ml hexane, 550 ml of a 1 molar solution of lithium-tri-sec.-butylborohydride in tetrahydrofuran are added in drops, so that the solution is maintained boiling. Following the completion of the addition, the mixture is heated to boiling for another hour. After cooling, the mixture is acidified by the drop-wise addition of methanolic hydrochloric acid. The methanol phase is then separated and the toluene/hexane mixture is again extracted with hydrochloric acid in methanol. The extracts are evaporated, taken up with dichloromethane and a solution (10%) of sodium carbonate, the organic phase washed with saturated sodium chloride, dried over sodium sulfate and evaporated to dryness. 67.6 g (70% of the theoretical yield) of rac.-2,3,4,5-tetrahydro-3-methylamino-1-benzoxepin-5-ol are obtained in the form of an oily residue, wherein rac.-cis-2,3,4,5-tetrahydro-3-methylamino-1-benzoxepin-5-ol predominates with 82 parts for 18 parts of rac.-trans-2,3,4,5 -tetrahydro-3-methylamino-1-benzoxepin-5-ol. The compounds may be separated and identified as described hereinabove.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C@@H:13]1[O:25][C@H:24]([CH2:26][O:27]C(=O)C)[C@@H:19]([O:20]C(=O)C)[C@H:14]1[O:15]C(=O)C)(=O)C.C(=O)([O-])O.[Na+].C[O-].[Na+].CO>C1(C)C=CC=CC=1.[Br-].[Zn+2].[Br-]>[CH2:1]([O:8][C@@H:13]1[O:25][C@H:24]([CH2:26][OH:27])[C@@H:19]([OH:20])[C@H:14]1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: OCc1ccccc1
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CO
Product: OC[C@H]1O[C@@H](OCc2ccccc2)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.2 %

Procedure:
Benzyl alcohol (2.07 mL, 20 mmol) was added to a solution of β-D-ribofuranose-1,2,3,5-tetraacetate (3.18 g, 10 mmol) and zinc bromide (2.25 g, 10 mmol) in toluene (31.8 mL), and the mixture was stirred at ambient temperature for 20 hours. To the resulting solution was added aqueous saturated sodium hydrogen carbonate solution (31.8 mL), for layer separation. To the resulting aqueous layer was added toluene (31.8 mL) for extraction. The resulting two organic layers were combined together, washed with aqueous saturated sodium chloride solution (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the resulting oily 1-O-benzyl-β-D-ribofuranose-2,3,5-triacetate were added methanol (31.8 mL) and a solution of 28% sodium methoxide in methanol (0.2 mL, 1 mmol), the mixture was stirred at ambient temperature for 2 hours, and the resulting mixture was concentrated under reduced pressure. The resulting oily matter was purified by silica gel column chromatography, to recover the desired 1-O-benzyl-β-D-ribofuranose (2.24 g; yield of 93.2%) as a white solid. Melting point: 95° C.
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6]1)[CH2:2][C:3]#[CH:4].Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][F:23])[N:17]=1>>[F:23][CH2:22][C:18]1[N:17]=[C:16]([C:4]#[C:3][CH2:2][CH2:1][N:5]2[C:13](=[O:14])[N:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]3=[N:6]2)[CH:21]=[CH:20][CH:19]=1
Reactant: C#CCCn1nc2ccccn2c1=O
Reactant: FCc1cccc(Br)n1
Product: O=c1n(CCC#Cc2cccc(CF)n2)nc2ccccn12

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (70 mg, 0.37 mmol, Example 39(A)) and 2-bromo-6(fluoromethyl)pyridine (78 mg, 0.41 mmol, Example 190(E)). The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 20 mg (67 μmol, 18%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl) [1,2,4]triazolo[4,3-a]pyridin-3(2H) one as an orange solid (M.P.=106-107° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[N:10]=[C:9]([CH2:12][O:13][CH3:14])[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Br[CH2:16][C:17]1[CH:36]=[CH:35][C:20]2/[C:21](=[C:31](/[CH3:34])\[C:32]#[N:33])/[C:22]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=3[O:24][CH2:25][C:19]=2[CH:18]=1>>[F:30][C:27]1[CH:28]=[CH:29][C:22]2=[C:23]([CH:26]=1)[O:24][CH2:25][C:19]1[CH:18]=[C:17]([CH2:16][N:8]3[C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=4[N:10]=[C:9]3[CH2:12][O:13][CH3:14])[CH:36]=[CH:35][C:20]=1/[C:21]/2=[C:31](/[CH3:34])\[C:32]#[N:33]
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: COCc1nc2c(OC)cccc2[nH]1
Product: COCc1nc2c(OC)cccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 53.2 %

Procedure:
[step 3] Using 4-methoxy-2-(methoxymethyl)-1H-benzo[d]imidazole (1.3 g, 6.8 mmol) obtained in step 2 and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (2.5 g, 7.0 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, (E)-2-(3-fluoro-8-{[4-methoxy-2-(methoxymethyl)-1H-benzo[d]imidazol-1-yl]methyl}dibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (1.7 g, 53%) was obtained.