Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9](SC)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27]([NH2:35])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CO>[C:21]([O:20][C:18]([N:10]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]1[NH:35][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: NCCc1ccccc1
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(NCCc2ccccc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 44.2 %

Procedure:
A mixture of intermediate 59 (2.0 g, 5.43 mmol), phenethylamine (2.04 mL, 16.3 mmol) and MeOH (0.5 mL) is heated at 100° C. for 2 days. The reaction mixture is cooled to RT, and is purified by chromatography on silica gel; gradient elution with heptane:EtOAc (75:25-60:40) gives 1.06 g of the product 93. 1H NMR (CDCl3) δ 7.40-7.30 (m, 4H), 7.30-7.10 (m, 2H), 7.10-6.90 (m, 8H), 6.80-6.65 (m, 2H), 5.45-5.25 (m, 2H), 3.90-3.60 (m, 2H), 3.05 (t, 2H), 1.13 (s, 9H); MS: m/z 442 (M++1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH3:29])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[S:19][CH:20]=[C:21]([CH2:23]Cl)[N:22]=4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.O>CCO>[Cl:1][C:2]1[C:3]([N:27]([CH3:28])[CH3:29])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[S:19][CH:20]=[C:21]([CH2:23][N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[N:22]=4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CCl)cs3)c1)=N2
Reactant: C1COCCN1
Solvent: O
Solvent: CCO
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CN4CCOCC4)cs3)c1)=N2
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 8-chloro-4-[3-(4-chloromethyl-thiazol-2-yl)-phenyl]-7-dimethylamino-1,3-dihydro-benzo[b][1,4]diazepin-2-one (89 mg) (Example 191a), morpholine (0.17 mL) and KI (3 mg) in EtOH (0.5 mL) was stirred at 60° C. for 3 h. H2O (25 mL) was added to the cooled solution and the precipitate was collected by filtration and purified by chromatography on silica gel using AcOEt/acetone (1:1) as eluent. The product was stirred with 20% aqueous MeOH (20 mL) The pH of the mixture was set to 11 by addition of 1N NaOH and the solid was subsequently isolated by filtration to give the title compound (55 mg) as yellow powder.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].CO.[CH2:14]([OH:16])C.C(Cl)(Cl)Cl>O.C(Cl)(Cl)Cl>[OH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]=1[CH:14]=[O:16]
Reactant: Oc1ccc2ccccc2c1
Reactant: CCO
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=Cc1c(O)ccc2ccccc12

Procedure:
In step (a), β-naphthol is preferably first added to an aqueous alcoholic alkaline medium, for instance a solution of an alkali metal hydroxide in a mixture of water and a C1-C4 aliphatic alcohol, especially methanol or ethanol, at an elevated temperature preferably at a temperature within the range of 70°-100° C. To the resulting pale brown emulsion, the chloroform reactant is then added slowly -- preferably dropwise -- at an elevated temperature, preferably 70°-100° C. After the addition of a few drops of chloroform, the reaction mixture assumes a blue colouration which is allowed to change to green before any further chloroform is added. Subsequently, chloroform is added slowly and at such a rate that the green colouration is maintained. After completion of the addition of chloroform, the alkali metal salt of 2-hydroxy-1-naphthaldehyde may be isolated e.g. by filtration, and washed, preferably with brine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=2)[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[NH:27])[NH:25][OH:26])=[CH:20][CH:19]=2)=[O:16])(=[O:10])=[O:9])[CH:7]=1.N1C=CC=CC=1.[S:39](Cl)(Cl)=[O:40]>O1CCCC1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=2)[C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[NH:27][S:39](=[O:40])[O:26][N:25]=3)=[CH:22][CH:23]=2)=[O:16])(=[O:10])=[O:9])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Nc1cccc(C(=O)Nc2ccc(C(=N)NO)cc2)c1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(Cl)cc1S(=O)(=O)Nc1cccc(C(=O)Nc2ccc(C3=NOS(=O)N3)cc2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 9.2 %

Procedure:
A solution of 3-(5-chloro-2-methoxy-benzenesulfonylamino)-N-[4-(N-hydroxycarbamimidoyl)-phenyl]-benzamide (110 mg, 0.23 mmol) in tetrahydrofuran (7.0 ml) under argon was treated with pyridine (37 mg, 2 equiv.) and cooled to 0° C. A solution of thionyl chloride (28 mg, 1.01 equiv.) in dichloromethane (1.0 ml) was then added dropwise in 6 min. The mixture was stirred at 0° C. for 20 min and then at room temperature for 45 min. The solvent was evaporated and the residue diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated. Purification via preparative HPLC (Column: ZORBAX ECLIPSE XDB-C18, 21.2×50 mm, 5 um, PN 970050-902, SN USDN001082. Gradient: 0-1.2 min: 10% CH3 CN in (water+0.1% HCO2H), 1.2-4.7 min: increasing of CH3CN from 10% to 95%, 4.7-5.7 min: 95% of CH3CN, 5.7-59 min: decreasing of CH3CN from 95% to 10%. Program end at 6 min. Flow:30 ml/min) yielded the title compound as a light green solid (11 mg, 9%), MS (ISP): m/e=519.1 (M−H).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[C:25]1[CH:26]=[CH:27][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:32])=[N:29][CH:30]=1)=O.[Br:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1.CC(O)=O>CCOC(C)=O.ClCCCl>[Br:41][C:42]1[CH:48]=[CH:47][C:45]([NH:46][CH2:15][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[C:25]2[CH:26]=[CH:27][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:32])=[N:29][CH:30]=2)=[CH:44][CH:43]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(OC)ccc2C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(OC)ccc2CNc2ccc(Br)cc2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (1.3 g, 6.0 mmol) was added to a DCE solution (5 mL) of ethyl 3-(5-(2-formyl-5-methoxyphenyl)picolinamido)propanoate (1.4 g, 4.0 mmol), 4-bromoaniline (1.0 g, 6.0 mmol), and AcOH (0.23 mL, 4.0 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture diluted with EtOAc washed with water and brine, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[CH:10][CH:11]=1
Reactant: [H][H]
Reactant: COC(=O)C=Cc1ccc(C)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc(C)cc1
Yield: 88.2 %

Procedure:
1.39 g of 3-p-tolyl-acrylic acid methyl ester (40aa) prepared by above Step 1 was dissolved in methanol solution (7.9 mM) under nitrogen atmosphere. Then Pd—C was added thereto, hydrogenated under a hydrogen balloon for 1 to 2 hrs at room temperature. The reaction mixture was filtered and concentrated in vacuo. The resulting compound was purified with Silica gel column chromatography with a solvent mixture mixed with EtOAc and hexane (1:10) as an eluant to give 1.24 g of 3-p-tolyl-propionic acid methyl ester (40ab) (yield: 95%).
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])=[CH:7][CH:6]=1)[CH2:3][CH3:4].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C1COCC1>[CH3:26][S:27]([O:1][CH:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])=[CH:9][N:10]=1)[CH2:3][CH3:4])(=[O:29])=[O:28]
Reactant: CCC(O)c1ccc(-c2ccccc2C#N)cn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(OS(C)(=O)=O)c1ccc(-c2ccccc2C#N)cn1
Reaction time: 0.08 h
Yield: 71 %

Procedure:
To solution of 2-(6-(1-hydroxypropyl)pyridin-3-yl)benzonitrile (0.05 g) in THF (3 mL) was added triethyl amine (0.042 g), the mixture was stirred for 5 minutes, and then methanesulfonyl chloride was added (0.47 g). The mixture was stirred at room temperature for 90 min. The reaction mixture was quenched with sodium bicarbonate and extracted with ethyl acetate. The organic extracts were dried over sodium sulphate, filtered and concentrated to obtain 1-(5-(2-cyanophenyl)pyridin-2-yl)propyl methanesulfonate (0.050 g, 71% yield), which was used directly in the next step.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:28])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[O:14][C:15]([C:18]3[S:19][C:20]([CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:21][CH:22]=3)=[N:16][N:17]=2)=[CH:8][C:7]=1[CH3:27].CCN(C(C)C)C(C)C.[C:38](O)(=[O:41])[CH2:39][OH:40].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl.CC(=O)OCC>[OH:41][CH2:38][C:39]([NH:1][CH2:2][CH:3]([OH:28])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[O:14][C:15]([C:18]3[S:19][C:20]([CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:21][CH:22]=3)=[N:16][N:17]=2)=[CH:8][C:7]=1[CH3:27])=[O:40]
Reactant: Cc1cc(-c2nnc(-c3ccc(CC(C)C)s3)o2)cc(C)c1OCC(O)CN
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nnc(-c3ccc(CC(C)C)s3)o2)cc(C)c1OCC(O)CNC(=O)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.9 %

Procedure:
To a solution of 1-amino-3-{4-[5-(5-isobutyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenoxy}-propan-2-ol (109 mg, 271 μmol) in DCM (10 mL), DIPEA (140 mg, 1.086 mmol) and glycolic acid (41 mg, 543 μmol) followed by TBTU (102 mg, 319 μmol) is added at 0° C. The mixture is stirred at rt for 1 h before it is diluted with EA and washed with water. The water phase is separated and extracted once more with EA. The combined org. extracts are dried over MgSO4, filtered and evaporated. The crude product is purified by chromatography on prep. TLC plates with DCM containing 4% of 7 N NH3 in methanol to give 2-hydroxy-N-(2-hydroxy-3-{4-[5-(5-isobutyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenoxy}-propyl)-acetamide (31 mg) as a white solid; LC-MS: tR=0.94 min, [M+1]+=460.51.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36](B(O)O)[CH:35]=1>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.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>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=4)([C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)[OH:20])[CH:8]=3)[N:3]=[C:2]([C:36]3[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=3)[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)nc(-c3cccc(Cl)c3)c2c1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(-c3cccnc3)nc(-c3cccc(Cl)c3)c2c1
Temperature: 115 °C
Reaction time: 3 h
Yield: 25.5 %

Procedure:
A mixture of 2-chloro-4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinazolinemethanol (0.0051 mol), described in International Patent Specification WO 00/39082, 3-pyridinyl-boronic acid (0.0077 mol) and Pd(PPh3)2Cl2 (0.001 mol) in sodium carbonate 2M (25 ml) and dioxane (25 ml) was stirred at 115° C. for 3 hours, then cooled, poured out into ice water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 1.02 g of a fraction which was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 0.7 g (36%) of 4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-2-(3-pyridinyl)-6-quinazolinemethanol, mp.178° C.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][C:10](=O)[NH:9][C:8](=O)[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C[OH:16].Cl.N.C1[CH2:23][O:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:23]([O:22][CH2:21][CH3:20])=[O:16])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C1Cc2cccc(Cl)c2CC(=O)N1
Reactant: C1CCOC1
Agent: Cl
Agent: N
Product: CCOC(=O)N1CCc2cccc(Cl)c2CC1
Reaction time: 2.5 h

Procedure:
To a solution of 22.5 g of 6-chloro-1H-3-benzazepine-2,4(3H,5H)-dione in 200 ml of THF were added dropwise 38 ml of a 10 M borane-dimethyl sulfide complex at 0° C. for 20 minutes, followed by stirring for 2.5 hours. The reaction mixture was heated and refluxed, and further stirred. To the reaction mixture was added dropwise 30 ml of MeOH under ice-cooling, followed by stirring, and then 30 ml of 4 M hydrochloric acid was added dropwise thereto, followed by heating and refluxing for 1 hour after generation of bubbles substantially settled. The mixture was alkalified by the addition of aqueous ammonia and a 1 M aqueous sodium hydroxide solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, the residue was dissolved in EtOH, and activated carbon was added thereto, followed by heating and refluxing, and then filtering on amino silica gel, and the filtrate was concentrated under reduced pressure. To a solution of 18.7 g of the resulting residue in 180 ml of dichloromethane was added 17 ml of pyridine, followed by ice-cooling, and 13 ml of ethyl chlorocarbonate was added dropwise thereto, followed by stirring for 1.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was diluted with EtOAc, then washed with 1 M hydrochloric acid and water, dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 9.653 g of ethyl 6-chloro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate as a reddish brown oily substance.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:17][C:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)=[N:15][N:14]=1.[C:27](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:27][N:23]1[C:24]2[C:20](=[CH:19][C:18]([C:16]3[O:17][C:13]([C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])=[N:14][N:15]=3)=[CH:26][CH:25]=2)[CH:21]=[CH:22]1
Reactant: O=C([O-])[O-]
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc3[nH]ccc3c2)o1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc3c(ccn3C)c2)o1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.7 %

Procedure:
To a solution of 5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1H-indole (150 mg, 0.44 mmol) in DMF (2 mL) was added potassium carbonate (121 mg, 0.88 mmol) and iodomethane (0.04 ml, 0.66 mmol) and the reaction mixture was stirred for 3 d in a closed round bottomed flask at ambient temperature. The mixture was extracted with water (20 ml) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with aqueous sodium carbonate (half saturated, 20 mL) and brine (20 mL). Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20) afforded the title compound (136 mg, 87%) as a white solid. MS: m/e=357.2 [M+H]+.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH2:4]1)=O.[OH:31][C:32]1([CH2:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[OH:31][C:32]1([CH2:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)[CH2:37][CH2:36][N:35]([CH2:1][C@@H:3]2[C@@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:6][N:5]([C@H:14]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:15]([OH:17])=[O:16])[CH2:4]2)[CH2:34][CH2:33]1
Reactant: OC1(CCCc2ccncc2)CCNCC1
Reactant: O=C[C@H]1CN([C@@H](C(=O)OCc2ccccc2)C2CCCCC2)C[C@@H]1c1ccccc1
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(O)(CCCc3ccncc3)CC2)[C@@H](c2ccccc2)C1

Procedure:
The title compound was prepared from 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, benzyl ester (from EXAMPLE 1, Step I) and 4-hydroxy-4-(3-(4-pyridyl)propyl)piperidine.HCl (from EXAMPLE 81, Step A) using procedures analogous to those described in EXAMPLE 71, Steps A and B. For the title compound: 1H NMR (500 MHz) δ 1.00-4.00 (35H), 7.04 (d, J=5.7, 2H), 7.24-7.31 (5H), 8.40 (d, J=5.7, 2H); ESI-MS 520 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.C(OCC)(=O)C.O>N1C=CC=CC=1>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:7])[CH3:1])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CCCO
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCCCC(C)C)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-methylpentanol (3.0 ml) in pyridine (20 ml) were added in turn with p-toluenesulfonyl chloride (4.6 g) and 4-N,N-dimethylaminopyridine (1.5 g) at ambient temperature. After stirring at ambient temperature, the reaction mixture was taken up into a mixture of ethyl acetate (100 ml) and water (100 ml). The separated organic layer was washed in turn with hydrochloric acid(1N), water, aqueous sodium hydrogencarbonate, and brine, and dried over magnesium sulfate. Evaporation gave 1-p-Toluenesulfonyloxy-4-methylpentane (5.30 g).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(C)C.C[Li].C1(O[C:23]#[N:24])C=CC=CC=1.Cl>CN(C)P(=O)(N(C)C)N(C)C.C(OCC)C.O1CCCC1>[OH:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]#[C:5][C:23]#[N:24])=[CH:8][CH:9]=1
Reactant: N#COc1ccccc1
Reactant: C[Si](C)(C)C#Cc1ccc(O)cc1
Agent: Cl
Agent: [Li]C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CC#Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
A solution of 381 mg of p-[(trimethylsilyl)ethynyl]phenol in 5 ml of hexamethylphosphoric acid triamide was treated at -5° C. in a sulphonation flask under argon gasification with 2.5 ml of a 1.75M solution of methyl lithium in diethyl ether. 15 minutes after completion of the addition the mixture, which had become a red slurry, was diluted with 5 ml of absolute tetrahydrofuran and subsequently stirred at room temperature for 3 hours. The mixture was then cooled to -30° C. and 322 μl of phenyl cyanate were added. The new brown-orange clear solution was warmed to 0° C. within 60 minutes, then poured into 50 ml of 1N hydrochloric acid and extracted three times with 50 ml of diethyl ether each time. The organic phases were washed a further three times with 50 ml of water each time (to which was added a small amount of sodium chloride solution), dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.4 bar) of the orange residue (570 mg) on silica gel with 15% ethyl acetate/petroleum ether followed by 20% ethyl acetate/petroleum ether gave 160 mg (56%) of (p-hydroxyphenyl)propiolonitrile as light yellowish crystals; m.p. 134°-137° C.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=[O:7])[O:5]1)#[N:2].[Na]>CO>[C:1]([CH:3]1[C:6](=[O:7])[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]1=[O:5])#[N:2]
Reactant: N#CC=C1OC(=O)c2ccccc21
Agent: [Na]
Solvent: CO
Product: N#CC1C(=O)c2ccccc2C1=O

Procedure:
3-Cyanomethylene phthalide (6.0 g.; 0.035 mole) was added to a solution of sodium (0.8 g.) in methanol (35 ml) and the red solution refluxed for 20 mins. On cooling and acidification with one-third of its bulk of concentrated hydrochloric acid the indandione separated as a copious yellow solid, m.p. 204°-207° C (d) (lit. m.p. 201°-202° C).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C@@H:14]([O:16][CH3:17])[CH3:15])[N:8]=[C:7]([CH3:18])[CH:6]=[CH:5]2.[O:19]1CCOCC1>O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C@@H:14]([O:16][CH3:17])[CH3:15])[N:8]=[C:7]([CH:18]=[O:19])[CH:6]=[CH:5]2
Reactant: C1COCCO1
Reactant: CO[C@@H](C)COc1cc2nc(C)ccc2cc1F
Solvent: O
Product: CO[C@@H](C)COc1cc2nc(C=O)ccc2cc1F
Yield: 85 %

Procedure:
To a solution of crude (S)-6-fluoro-7-(2-methoxypropoxy)-2-methylquinoline (0.281 g, 1.13 mmol) in dioxane (4 mL) and water (0.04 mL) was added SeO2 (0.138 g, 1.24 mmol). The reaction mixture was heated at reflux for 3 hours. After cooling, the mixture was filtered through Celite®. The filtrate was concentrated. The residue was purified by flash chromatography on silica gel (hexanes:EtOAc, 4:1) to give (S)-6-fluoro-7-(2-methoxypropoxy)quinoline-2-carbaldehyde (0.251 g, 85% for two steps) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[NH2:12][C:13]([NH2:15])=[S:14].[I:16]I>>[IH:16].[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[C:7]3[N:12]=[C:13]([NH2:15])[S:14][C:6]=3[CH2:5][C:4]=2[CH:3]=1
Reactant: O=C1CCc2cc(Cl)ccc21
Reactant: NC(N)=S
Reactant: II
Product: I
Product: Nc1nc2c(s1)Cc1cc(Cl)ccc1-2
Temperature: 100 °C
Reaction time: 1 h
Yield: 28.5 %

Procedure:
A mixture of 5-chloro-1-indanone (1.00 g; 6.00 mmol), thiourea (0.917 g; 12.0 mmol) and iodine (1.55 g; 6.10 mmol) was heated to 100° C. in a sealed tube. After 1 hr., the mixture was allowed to cool to room temperature. The solid was triturated with water and filtered. The solid was then triturated with absolute ethanol, filtered and washed several times with absolute ethanol to provide 0.60 g of 6-Chloro-8H-indeno[1,2-d]thiazol-2-ylamine hydroiodide 10.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:3]=1[CH3:20].[NH2:21][C:22]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25].Cl.O1CCOCC1>CO>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:21][C:22]3[CH:29]=[C:28]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)[CH:27]=[CH:26][C:23]=3[C:24]#[N:25])=[C:3]([CH3:20])[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1c(-c2ccccc2F)nc2cc(F)ccc2c1Cl
Reactant: N#Cc1ccc(N2CCOCC2)cc1N
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(-c2ccccc2F)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)ccc1C#N

Procedure:
Prepared according to general Procedure K using 4-chloro-7-fluoro-2-(2-fluorophenyl)-3-methylquinoline (70 mg, 0.24 mmol), 2-amino-4-morpholinobenzonitrile (49 mg, 0.24 mmol) and a 4.0M solution of HCl in dioxane (0.030 mL, 0.121 mmol) in MeOH (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification 2-((7-fluoro-2-(2-fluorophenyl)-3-methyl-4-quinolinyl)amino)-4-(4-morpholinyl)benzonitrile was obtained as a yellow film. 1H NMR (500 MHz, chloroform-d) δ ppm 7.94-8.03 (1H, m), 7.82 (1H, dd, J=9.8, 2.7 Hz), 7.60-7.66 (1H, m), 7.43-7.52 (2H, m), 7.32-7.40 (2H, m), 7.13-7.22 (1H, m), 6.56 (1H, br. s.), 6.41 (1H, dd, J=8.8, 2.2 Hz), 5.81 (1H, d, J=2.7 Hz), 3.68-3.77 (4H, m), 2.98-3.15 (4H, m), 2.12-2.26 (3H, s). Mass Spectrum (ESI) m/e=457.0 (M+1).