Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[N:3]=[CH:4][C:5]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)=[N:6][C:7]=1C.[CH3:17]C1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:33][C:34]1[CH:35]=[CH:36][C:37]([N:43]2[N:47]=[CH:46][CH:45]=[N:44]2)=[C:38]([CH:42]=1)[C:39](O)=[O:40].S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[F:33][C:34]1[CH:35]=[CH:36][C:37]([N:43]2[N:47]=[CH:46][CH:45]=[N:44]2)=[C:38]([C:39]([N:14]2[CH2:13][CH2:12][C@@H:11]3[C@@H:16]([N:9]([C:5]4[C:4]([CH3:17])=[N:3][CH:2]=[CH:7][N:6]=4)[CH2:10]3)[CH2:15]2)=[O:40])[CH:42]=1
Reactant: Cc1ncc(N2C[C@@H]3CCNC[C@@H]32)nc1C
Reactant: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: Cc1nccnc1N1C[C@@H]2CCN(C(=O)c3cc(F)ccc3-n3nccn3)C[C@@H]21

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-8-(3-methylpyrazin-2-yl)-3,8-diazabicyclo[4.2.0]octane (Intermediate 31) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 5-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 13) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C20H20FN7O, 393.43; m/z found 394.1 [M+H]+. 1H NMR (CD3OD): 8.10-8.01 (m, 1H), 7.97-7.88 (m, 2H), 7.83-7.74 (m, 1H), 7.67-7.61 (m, 1H), 7.47-7.22 (m, 2H), 4.52-4.30 (m, 2H), 4.22-3.83 (m, 2H), 3.75-3.11 (m, 3H), 2.72-2.31 (m, 4H), 2.18-1.50 (m, 2H).
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([CH3:19])[CH3:18])=[C:12]([O:20][CH3:21])[CH:11]=1)=O)=O.O=P(Cl)(Cl)Cl>C(#N)C>[CH:17]([O:16][C:13]1[CH:14]=[C:15]2[C:10]([CH2:9][CH2:8][N:7]3[CH:1]=[N:3][CH:4]=[C:5]32)=[CH:11][C:12]=1[O:20][CH3:21])([CH3:19])[CH3:18]
Reactant: COc1cc(CCNC(=O)CNC=O)ccc1OC(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1cc2c(cc1OC(C)C)-c1cncn1CC2
Temperature: 80 °C
Yield: 34.5 %

Procedure:
To a 50 mL round bottom flask was added 2-formamido-N-(4-isopropoxy-3-methoxyphenethyl)acetamide (600 mg, 2.04 mmol) followed by acetonitrile (10.2 mL) and POCl3 (0.57 mL, 6.12 mmol). The reaction mixture was heated to 80° C. for one hour then concentrated in vacuo. To the resulting oil was added H2O and aqueous saturated sodium carbonate, then the solution was extracted with EtOAc (2×). The organic extracts were combined, dried with sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-10% MeOH in DCM) to afford 9-isopropoxy-8-methoxy-5,6-dihydroimidazo[5,1-a]isoquinoline (182 mg) MS [M+H+]=259.2.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1.CN(C=O)C>[CH:22]1([NH:28][C:16](=[O:18])[C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:14]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Reactant: NC1CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Oxalyl chloride (132 μL, 1.5 mmol) was added over a 10 minute period to a mixture of 3-phenylbenzoic acid (200 mg, 1 mmol) dissolved in a mixture THF/DMF (3.5 mL/58 μL). After the addition, the reaction was stirred at room temperature for 2.5 hours. Cyclohexylamine (286 μL, 2.5 mmol) was then added into half of the acid chloride solution at 0° C. The reaction was then stirred at room temperature for 18 hours. The reaction was concentrated and water was added to the residue. The aqueous phase was extracted 3 times with CH2Cl2 and the combined organic layers were washed with 2N HCl, saturated NaHCO3, brine, dried over Na2SO4 and concentrated. Diethyl ether was added to the residue and a white solid precipitated which was collected by filtration and rinsed with a small amount of diethyl ether. The white solid was then dried under vacuum (108 mg, 80%). NMR 1H (ppm, CDCl3): 7.95 (s, 1H), 7.68 (d, J3=7.82 Hz, 2H), 7.59 (d, J3=7.13 Hz, 2H), 7.49-7.33 (m, 4H), 6.05 (br. d., J3=6.58 Hz, 1H), 3.75-3.70 (m, 1H), 2.06-2.01 (m, 2H), 1.78-1.61 (m, 3H), 1.49-1.36 (m, 2H), 1.30-1.14 (m, 3H).
Reaction SMILES: [CH3:1][S:2][CH:3]([S:16][CH3:17])[C:4]1([O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]([OH:9])[C@H:6]1[OH:7])[OH:5].[CH2:18](O)C1OC(=O)C(O)C(O)C1O.CSC([Li])SC>>[S:2]1[CH2:1][CH2:18][CH2:17][S:16][CH:3]1[C:4]1([O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]([OH:9])[C@H:6]1[OH:7])[OH:5]
Reactant: O=C1OC(CO)C(O)C(O)C1O
Reactant: CSC(SC)C1(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: [Li]C(SC)SC
Product: OC[C@H]1OC(O)(C2SCCCS2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
Process 1", i.e. a process to produce, for example, 1-C-[bis(methylthio)methyl]-D-glucopyranose derivative (2") from D-glucono-δ-lactone derivative (1"), is conducted by allowing the compound (1") to react with bis(methylthio)methyllithium, or a process to produce 1-C-(1,3-dithian-2-yl)-D-glucopyranose (2"), is conducted by allowing the compound (1") to react with 2-lithio-1,3-dithiane. In this reaction, usually 1 to 5 mole equivalents, preferably 2-2.5 mole equivalents, of bis(methylthio)methyllithium or 2-lithio-1,3-dithiane for D-glucono-δ-lactone derivative (1") is used. This reaction is conducted in an appropriate solvent which is inactive to this reaction, such as tetrahydrofuran, 1,4-dioxane, ethyl ether, and hexane, which are used separately or in combination, preferably in an atmosphere of an inert gas such as nitrogen and argon. Reaction temperature is usually -20° C. --78° C., preferably -50° C.--78° C. in the initial stage of the reaction and -20° C.--40° C. in the later stage. Reaction time is appropriately about 1-8 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:32])[C:18]=1[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)=[O:21]>>[Cl:32][C:17]1[CH:16]=[N:15][CH:14]=[C:13]([Cl:12])[C:18]=1/[CH:19]=[C:20](\[O:21][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)/[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)O/C(=C\c2c(Cl)cncc2Cl)c2ccc(OC)c(OC)c2)cc1

Procedure:
The compound was obtained starting from 4-methoxy-benzoyl chloride and 2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethanone, following the procedure of Example 7.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[C:14]3[C:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)=[C:20]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:7]=1.[OH-].[Na+].Cl>O1CCOCC1>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:21]2[C:14]3[C:13]([O:12][C:8]4[CH:7]=[C:6]([NH:5][CH2:4][C:3]([OH:36])=[O:2])[CH:11]=[CH:10][CH:9]=4)=[N:18][CH:17]=[N:16][C:15]=3[O:19][C:20]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:27][CH:26]=1
Reactant: COC(=O)CNc1cccc(Oc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Oc4cccc(NCC(=O)O)c4)c23)cc1

Procedure:
Stir 65 mg (0.135 mmol) of N-(3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}-phenyl)glycine methyl ester, 0.27 ml of 1N sodium hydroxide solution and 2 ml of dioxane at RT overnight. Acidify the mixture with 1N hydrochloric acid and extract repeatedly with ethyl acetate/dichloromethane (1:1). Dry the combined organic phases over magnesium sulphate and concentrate. Chromatograph the residue on silica gel (eluent: dichloromethane/methanol 100:1→50:1). 16.8 mg (13.8% of theory) of the target compound are obtained as a yellowish hard oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=3)=[N:10][N:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30][C:31](Cl)=[O:32]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH:24][C:31](=[O:32])[CH2:30][C:26]4[S:25][CH:29]=[CH:28][CH:27]=4)[CH:21]=[CH:22][CH:23]=3)=[N:10][N:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: Cc1ccc2c(-c3ccnc(Cl)n3)c(-c3cccc(N)c3)nn2c1
Solvent: C1CCOC1
Product: Cc1ccc2c(-c3ccnc(Cl)n3)c(-c3cccc(NC(=O)Cc4cccs4)c3)nn2c1
Reaction time: 16 h
Yield: 89.3 %

Procedure:
{3-[3-(2-Chloro-4-pyrimidinyl)-6-methylpyrazolo[1,5-a]pyridin-2-yl]phenyl}amine (0.57 g, 1.68 mmol) and 2-thienylacetyl chloride (0.25 mL, 2.00 mmol) were stirred in THF (30 mL) and stirred for 16 h. Additional 2-thienylacetyl chloride was added until reaction was complete by LC/MS. The mixture was concentrated to dryness and partitioned between aqueous NaHCO3 (saturated) and DCM. The organic layers were concentrated and purified by column chromatography to afford N-{3-[3-(2-chloro-4-pyrimidinyl)-6-methylpyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide as a yellow solid (0.69 g, 89%). ES-LC/MS m/z=460 [M+H]+.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:16])[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=2)[CH2:3][CH2:2]1.C([SiH](CC)CC)C>CO.[Pd]>[NH2:13][C:9]1[CH:8]=[C:7]([CH2:6][C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:16])[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cc1cccc([N+](=O)[O-])c1)NC1CC1
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: CO
Product: Nc1cccc(CC(=O)NC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a stirred solution of N-cyclopropyl-2-(3-nitrophenyl)acetamide (2.4 g, 10.90 mmol) in methanol (25.0 ml) was added slurry of Pd/C (10%, 0.232 g), To the above reaction mixture, triethylsilane (8.70 ml, 54.5 mmol) was added slowly drop wise at room temperature (reaction was exothermic) and then the reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite bed and the filtrate was evaporated under vacuum. The residue was triturated in hexane, the solid obtained was filtered and dried under vacuum to give the product (1.95 gm).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([CH3:23])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:22])[NH:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:9]=1)[CH3:6])[CH3:2].[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([O:41][CH2:42][CH3:43])[C:35]=1[N:36]1[CH:40]=[CH:39][CH:38]=[CH:37]1)[CH:31]=O)[CH3:26].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:24])[C:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:22])[NH:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:31][C:30]3[CH:33]=[C:34]([O:41][CH2:42][CH3:43])[C:35]([N:36]4[CH:40]=[CH:39][CH:38]=[CH:37]4)=[C:28]([O:27][CH2:25][CH3:26])[CH:29]=3)[CH2:20][CH2:21]2)[CH:9]=1)([CH3:23])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C(=O)NC2CCNCC2)c1
Reactant: CCOc1cc(C=O)cc(OCC)c1-n1cccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(C)Oc1cccc(C(=O)NC2CCN(Cc3cc(OCC)c(-n4cccc4)c(OCC)c3)CC2)c1

Procedure:
In analogy to the procedure described in example 50k), 2-methyl-2-[3-(piperidin-4-ylcarbamoyl)-phenoxy]-propionic acid ethyl ester (example 50i) was reacted with 3,5-diethoxy-4-pyrrol-1-yl-benzaldehyde (example 40b), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless foam. MS: 578.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[Cl:1][C:2]1[CH:7]=[C:6]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1Cl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1Cl
Temperature: 70 °C
Yield: 68.4 %

Procedure:
To a solution of 2-chloro-4-fluoro-1-nitrobenzene (500 mg, 2.85 mmol) in MeCN (10 mL) was added morpholine (0.62 mL, 7.12 mmol) and potassium carbonate (394 mg, 2.85 mmol). The reaction mixture was heated at 70° C. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (30 mL) and washed with water (2×30 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-50% EtOAc in cyclohexane to afford the title compound (473 mg, 68%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:3]=12.[Cl:17][CH2:18][C:19]#[N:20]>>[ClH:17].[ClH:17].[CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][N:14]([CH2:18][C:19]#[N:20])[CH2:15][CH2:16][C:3]=12
Reactant: Cc1c2c(nc3ccccc13)CCNCC2
Reactant: N#CCCl
Product: Cc1c2c(nc3ccccc13)CCN(CC#N)CC2
Product: Cl
Yield: 25 %

Procedure:
2-[1,2,4,5-Tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline-3-yl]acetonitrile dihydrochloride was prepared from 1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline and chloroacetonitrile analogous to Example 186.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:32]>>[ClH:15].[ClH:31].[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:22]([CH3:21])[CH2:23][CH2:24][C:25]3[C:26]([Cl:32])=[CH:27][CH:28]=[CH:29][C:30]=3[Cl:31])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNCCc1c(Cl)cccc1Cl
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1c(Cl)cccc1Cl)CC2
Product: Cl

Procedure:
This compound was prepared analogous to Example 5(b) by reacting 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane with N-methyl-N-[2-(2,6-dichloro-phenyl)-ethyl]-amine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:15]#[C:16][Si](C)(C)C)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:15]#[CH:16])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(C#C[Si](C)(C)C)NS(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#CC(NS(C)(=O)=O)c1c(C)noc1-c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-{1-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-3-trimethylsilanyl-prop-2-ynyl}-methanesulfonamide (from previous step) was dissolved in THF (10 mL) and the mixture was cooled to 0° C. Tetrabutylammonium fluoride (1.0M in THF, 0.3 mL, 0.3 mmol) was added and the reaction stirred at 0° C. for 1 hour. The reaction was then submitted to standard aqueous workup and purified on silica gel (0-70% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [OH-].[K+].[SH:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][SH:9].Br[CH2:11][CH2:12][OH:13].[CH:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1)=[CH2:15]>C(O)C>[CH:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][S:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][S:9][CH2:11][CH2:12][OH:13])=[CH:18][CH:17]=1)=[CH2:15]
Reactant: SCCOCCS
Reactant: OCCBr
Reactant: C=Cc1ccc(CCl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=Cc1ccc(CSCCOCCSCCO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
To a solution of potassium hydroxide (48 g, 0.72 molar) in ethanol (1 liter) was added bis(2-mercaptoethyl)ether (100 g, 0.72 moles) and the mixture was stirred for 30 minutes at ambient temperature. Then 2-bromoethanol (90 g, 0.72 mole) was added to the mixture all at once and stirring was continued at ambient temperature for 30 minutes, then potassium hydroxide (48.0 g, 0.72 mole) was added to the mixture and again stirring was continued at ambient temperature for 30 minutes. p-Vinylbenzyl chloride (110 g, 0.72, mole) was then added all at once and stirred at room temperature for 16 hours. The next day the reaction was filtered and the solvent removed on a rotary evaporator. To the residue was added dichloromethane (1.2 liter), the mixture was washed with water (200 ml), 5% hydrochloric acid (200 ml), saturated sodium chloride (200 ml) then dried over anhydrous magnesium sulfate, filtered and the solvent removed in a rotary evaporator. To the residue was added diethyl ether (350 ml) and hexane (200 ml) and then the mixture was cooled in the freezer, filtered to give a white solid (94 g). Chromotography of the mother liquors gave additional product (48 g). Yield of 66%. Analysis calculated for C15H22O2S2. C, 60.36, H, 7.43, S, 21.49. Found: C, 60.41, H, 7.43, S, 21.14. 1H NMR (CDCl3) δ 2.7 (m, 6H, CH2S--CH2 +SCH2). 3.0-3.8 (m, 9H, ArCH2S, CH2OCH2,CH2OH), 5.15+5.65 (AB quartet, 2H, CH2 =), 6.68 (m, 1H, CH=), 7.25 (m, 4H, ArH's).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:19]([OH:21])=O)[C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.C(Cl)(=O)C(Cl)=O.[I:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:11]([C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)[C:19](=[O:21])[NH:34][C:33]2[CH:35]=[CH:36][C:30]([I:29])=[CH:31][CH:32]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(CC(C(=O)O)c2ccc(O)cc2)cc1
Reactant: Nc1ccc(I)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(CC(C(=O)Nc2ccc(I)cc2)c2ccc(O)cc2)cc1
Reaction time: 14 h
Yield: 63.8 %

Procedure:
To a stirred suspension of 4-[2-carboxy-2-(4-hydroxy-phenyl)-ethyl]-benzoic acid methyl ester (Step C, 1.5 g, 5.0 mmol) in anhydrous CH2Cl2 (10 mL), was added oxalylchloride (1.57 g, 12.5 mmol) at rt, the reaction mixture was stirred for 14 h. The reaction mixture was concentrated under reduced pressure and azeotroped with CH2Cl2 (2×10 mL) dried under vacuum for 3 h, The crude acid chloride (1.8 g, 5.66 mmol) was treated with 4-iodoaniline (1.48 g, 6.79 mmol) and N,N-diispropylethylamine (3.0 mL, 16.9 mmol) in CH2Cl2 at 0° C. The reaction mixture was stirred for 14 h at rt and the reaction mixture was concentrated under reduced pressure. The mixture was extracted with ethyl acetate (100 mL) and the organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was treated with CH2Cl2 to get solid compound, which was filtered and washed with CH2Cl2 to give 4-[2-(4-hydroxy-phenyl)-2-(4-iodo-phenyl-carbamoyl)-ethyl]-benzoic acid methyl ester as a yellowish solid (1.6 g, 64%): 1H NMR (300 MHz, DMSO-d6): δ 10.05 (s, 1H, NH), 9.28 (s, 1H, OH), 7.81 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.7 Hz, 2H), 7.31 (t, J=8.4 Hz, 4H), 7.18 (d, J=8.4 Hz, 2H), 6.65 (d, J=8.4 Hz, 2H), 3.85 (t, J=6.9 Hz, 1H), 3.77 (s, 3H), 3.40-3.36 (m, 1H), 2.95 (dd, J=6.0, 12.9 Hz, 1H); TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate/hexanes (1:2); Rf=0.5.
Reaction SMILES: Cl[CH2:2][CH:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1.[C:9]1([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]\[C:24]([OH:26])=[O:25]>>[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]\[C:24]([OH:26])=[O:25].[C:9]1([N:15]2[CH2:20][CH2:19][N:18]([CH2:2][CH:3]3[O:7][C:6](=[O:8])[NH:5][CH2:4]3)[CH2:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1NCC(CCl)O1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C(O)/C=C\C(=O)O
Product: O=C1NCC(CN2CCN(c3ccccc3)CC2)O1

Procedure:
Following the procedure of Example 35, the free base was prepared from 5-chloromethyl-2-oxazolidinone and 1-phenylpiperazine. The product was converted to the maleic acid salt, mp 166°-168° C.
Reaction SMILES: [CH2:1]([N:4]1[C:8]([CH:9]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:10][CH:11]=C)=[N:7][C:6]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([Cl:32])[N:29]=[CH:28]3)=[C:23]([O:33][CH3:34])[CH:22]=2)=[N:5]1)[CH:2]=C.C(O)(C(F)(F)F)=O>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.ClCCCl>[Cl:32][C:30]1[N:29]=[CH:28][N:27]([C:24]2[CH:25]=[CH:26][C:21]([NH:20][C:6]3[N:7]=[C:8]4[CH:9]([C:13]5[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=5)[CH2:10][CH:11]=[CH:2][CH2:1][N:4]4[N:5]=3)=[CH:22][C:23]=2[O:33][CH3:34])[CH:31]=1
Reactant: C=CCC(c1ccc(F)cc1)c1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nn1CC=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Nc2nc3n(n2)CC=CCC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Temperature: 70 °C
Yield: 13 %

Procedure:
Hoveyda-Grubbs Catalyst 2nd Generation (109 mg, 0.173 mmol) was added to a solution of 1-allyl-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-5-(1-(4-fluorophenyl)but-3-enyl)-1H-1,2,4-triazol-3-amine, TFA (410 mg, 0.691 mmol) in DCE (50.0 mL). The flask was flushed with nitrogen, sealed, and heated at 70° C. for 72 h. The reaction mixture was cooled to rt and an additional portion of Hoveyda-Grubbs Catalyst 2nd Generation (109 mg, 0.173 mmol) was added. The mixture was flushed with nitrogen, sealed, and heated at 70° C. for an additional 24 h. The crude reaction contents were directly loaded onto silica gel and the product was purified using silica gel column chromatography (10-75% EtOAc/chloroform, linear gradient) to afford (Z)—N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine (40 mg, 13% yield) as a solid. LC-MS (M+H)+ 451.1. 1H NMR (500 MHz, chloroform-d) δ ppm 7.52 (d, J=1.53 Hz, 1 H) 7.40 (d, J=2.14 Hz, 1 H) 7.24 (dd, J=8.55, 5.19 Hz, 2 H) 7.09 (d, J=8.55 Hz, 1 H) 7.01-7.07 (m, 3 H) 6.86 (dd, J=8.39, 2.29 Hz, 1 H) 6.78 (s, 1 H) 5.94-6.05 (m, 1 H) 5.84-5.94 (m, 1 H) 4.84 (dt, J=17.70, 2.14 Hz, 1 H) 4.57-4.66 (m, 1 H) 4.50 (dd, J=8.39, 3.51 Hz, 1 H) 3.80 (s, 3 H) 2.82-2.95 (m, 1 H) 2.71-2.82 (m, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:10]2[C:18]3[C:13](=[C:14]([O:19]CC4C=CC=CC=4)[CH:15]=[CH:16][CH:17]=3)[CH:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br>C(Cl)Cl>[OH:8][C:7]1[CH:6]=[CH:5][C:4]([N:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:19])[C:13]=3[CH:12]=[N:11]2)=[CH:3][C:2]=1[CH3:1]
Reactant: COc1ccc(-n2ncc3c(OCc4ccccc4)cccc32)cc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(-n2ncc3c(O)cccc32)ccc1O
Temperature: -78 °C
Yield: 9.1 %

Procedure:
1-[3-Methyl-4-(methyloxy)phenyl]-4-[(phenylmethyl)oxy]-1H-indazole (D34) (550 mg, 1.64 mmol) was dissolved in dry DCM (20 mL) and degassed by sonication under a flow of argon. The solution was cooled to −78° C. and after 10 mins treated with BBr3 (1M in DCM, 3.29 mL, 3.29 mmol) dropwise and when the addition was complete the bath was removed and it was allowed to reach room temperature. The reaction was followed by LC-MS. After 45 minutes more BBr3 (1M in DCM, 3.29 mL, 3.29 mmol) was added to the mixture and after 17 hours it was partitioned between DCM (75 mL)/water (75 mL), the pH adjusted to 7 by addition of a solution of NaHCO3 and the layers separated. The aqueous phase was extracted with DCM (2×50 mL) twice and the combined organics were washed with brine (50 mL) and dried over MgSO4, filtered and concentrated in vacuo. The crude material (456 mg) was purified by flash chromatography (Biotage SP4) with a gradient of EtOAc 0 to 40% in hexane. The isolated material was further purified by MDAP to afford 36 mg of the title compound (E18).