Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN([CH:4]=[CH:5][C:6]([CH:8]1[CH2:10][CH2:9]1)=O)C.[N+:11]([CH2:14][C:15]([NH2:17])=[O:16])([O-:13])=[O:12].C([O-])(=O)C.[NH2+]1CCCCC1>O>[CH:8]1([C:6]2[NH:17][C:15](=[O:16])[C:14]([N+:11]([O-:13])=[O:12])=[CH:4][CH:5]=2)[CH2:9][CH2:10]1
Reactant: NC(=O)C[N+](=O)[O-]
Reactant: CN(C)C=CC(=O)C1CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: O
Product: O=c1[nH]c(C2CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of crude β-N,N-dimethylaminoethenylcyclopropyl ketone (17-2; 12 g, <86 mmol), nitroacetamide (9 g, 86 mmol) and aqueous piperidinium acetate (10 ml) [prepared from glacial acetic acid (42 ml), water (100 ml) and piperidine (72 ml)] was stirred at room temperature overnight. Following dilution with water (20 ml), the yellow precipitate was isolated via filtration and drying in vacuo to yield the title compound 17-3: 1H NMR (CDCl3) δ 1.15 (m, 2 H), 1.36 (m, 2 H), 2.10 (m, 1 H), 6.02 (br d, J=8.0 Hz, 1 H), 8.41 (d, J=8.0 Hz, 1 H).
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][N:14]=[C:13]([O:16][CH2:17][CH:18]3[O:20][CH2:19]3)[C:12]=2[CH:21]=1.O>C(#N)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][N:14]=[C:13]([O:16][CH2:17][CH:18]([OH:20])[CH2:19][OH:2])[C:12]=2[CH:21]=1
Reactant: Clc1ccc2onc(OCC3CO3)c2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: OCC(O)COc1noc2ccc(Cl)cc12
Yield: 74.2 %

Procedure:
256 ml of a 10% w/v aqueous solution of potassium carbonate were added to a suspension of 21.0 g (92.7 mmoles) of 5-chloro-3-(2,3-epoxypropoxy)-1,2-benzisoxazole (prepared according to the method described in Japanese Patent Provisional Publication No. Sho. 52-31070) in 100 ml of acetonitrile, and the mixture was then heated under reflux for 3 hours. At the end of this time, the reaction mixture was cooled by allowing it to stand, and then 500 ml of water were added. The reaction mixture was then extracted with 1 liter of ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was removed by distillation to give a solid residue. This was then recrystallized from a mixture of ethyl acetate and diethyl ether, to give 16.7 g (yield 74.2%) of the title compound as a colorless amorphous powder, melting at 61°-62° C.
Reaction SMILES: [OH:1][C:2]([CH3:18])([CH3:17])[CH2:3][O:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11]CC)=[O:10])=[CH:7][C:6]=1[CH3:16].[OH-].[Na+]>C(O)C.O>[OH:1][C:2]([CH3:18])([CH3:17])[CH2:3][O:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[CH3:16]
Reactant: CCOC(=O)c1ccc(OCC(C)(C)O)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)O)ccc1OCC(C)(C)O
Temperature: 40 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
A mixture of 1-chloro-2-methyl-propan-2-ol (10 mL), 4-hydroxy-3-methyl-benzoic acid (2.0 g, 13.15 mmol), potassium carbonate (7.3 g, 52.71 mmol), water (6 mL) and ethanol (60 mL) was heated at 80° C. for 16 hours. The reaction mixture was cooled to room temperature and partitioned between 1N NaOH and EtOAc and the layers were separated. The organic layer was washed with 1N NaOH (2×10 mL) and the combined aqueous layers were washed with EtOAc. The combined organic layers were dried and concentrated in vacuo to give ethyl 4-(2-hydroxy-2-methyl-propoxy)-3-methyl-benzoate. The ester was dissolved in ethanol (15 mL) and water (2 mL), sodium hydroxide (1.1 g, 26.30 mmol) was added and the reaction mixture was stirred at 40° C. for 4 hours. The reaction mixture was poured into 1N NaOH solution and extracted with ether (2×10 mL). The aqueous layer was acidified to pH 2-3 using 6N HCl solution and extracted with EtOAc (3×10 mL). The organics were separated and washed with brine solution. The organic layer was dried (Na2SO4) and concentrated in vacuo and the resulting material was triturated with ether to give 4-(2-hydroxy-2-methyl-propoxy)-3-methyl-benzoic acid (2.2 g, 75%) as a white solid. ESI-MS m/z calc. 224.1. found 225.5 (M+1)+; Retention time: 1.06 minutes (3 min run) 1H NMR (400 MHz, DMSO) δ 7.75 (dd, J=8.5, 2.0 Hz, 1H), 7.73-7.70 (m, 1H), 6.96 (d, J=8.6 Hz, 1H), 4.67 (s, 1H, OH), 3.76 (s, 2H), 2.20 (s, 3H), 1.22 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][N:18]=2)[C:15]([NH2:19])=[N:14][CH:13]=[CH:12]3)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:48])[C:39]1[C:40](=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:41](Cl)=[O:42]>ClCCl>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:30][CH:29]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][N:18]=2)[C:15]([N:19]2[C:41](=[O:42])[C:40]4[C:39](=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:38]2=[O:48])=[N:14][CH:13]=[CH:12]3)=[CH:22][CH:23]=1
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc3ccnc(N)c3cn2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc3ccnc(N4C(=O)c5ccccc5C4=O)c3cn2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred mixture of crude 4-5 (10.9 g, <19.3 mmol), triethylamine (8.05 mL, 57.8 mmol), and dichloromethane (75.0 mL) at 0° C. under an atmosphere of nitrogen gas was added phthaloyl dichloride (90%; 3.75 mL, 23.4 mmol). The resulting mixture was stirred at ambient temperature for 15 hours under an atmosphere of nitrogen gas. The reaction mixture was quenched with saturated aqueous NH4Cl (200 mL) and the resulting mixture was extracted with dichloromethane (1000 mL, 500 mL×2). The combined organic extracts were washed with brine (200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel 200 g, step gradient eluting with 50:1, 40:1, 30:1, 20:1, 10:1, and 5:1 dichloromethane/ethyl acetate) followed by recrystallization from dichloromethane to give 3.94 g (39% in 3 steps) of 4-6 as yellow crystals: 1H NMR (400 MHz, CDCl3) δ 8.94 (1H, br s), 8.33 (1H, d, J=6.0 Hz), 8.02 (2H, m), 7.84 (2H, m), 7.31 (1H, dd, J=6.0, 0.8 Hz), 7.15 (4H, m), 6.85 (4H, m), 6.52 (1H, br s), 4.81 (4H, br s), 3.79 (6H, s); ESI-MS m/z 531 [C32H26N4O4+H]+.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([F:20])([F:19])[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]([F:9])([F:19])[F:20])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.6 %

Procedure:
Benzyl bromide (66.17 ml, 95.35 g, 0.56 mol) was added to a mixture of 4-(trifluoromethoxy)phenol (90.26 g, 0.51 mol) and potassium carbonate (140.97 g, 1.2 mol) in dimethylformamide (160 ml) and the mixture was stirred at room temperature for 72 hours. The mixture was poured into water (1.5 l) and extracted with ethyl acetate (3×500 ml). The combined organic fractions were washed with aqueous sodium carbonate (saturated, 500 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (133.5 g, 99%). 1H NMR (360 MHz, CDCl3)δ7.39 (5H, m), 7.14 (2H, d, J=9.0 Hz), 6.95 (2H, d, J=9.0 Hz), and 5.05 (2H, s).
Reaction SMILES: C([Li])CCC.[CH2:6]([N:9]([CH2:13][C:14]#[CH:15])[CH2:10][CH2:11][CH3:12])[CH2:7][CH3:8].[CH2:16]([N:18]1[C:26]2[N:25]=[CH:24][N:23]([CH2:27][CH2:28][CH3:29])[C:22]=2[C:21](=[O:30])[N:20]([CH2:31][CH2:32][CH2:33][C:34](=[O:36])[CH3:35])[C:19]1=[O:37])[CH3:17].Cl>CCCCCC.O1CCCC1>[CH2:13]([N:9]([CH2:10][CH2:11][CH3:12])[CH2:6][C:7]#[C:8][C:34]([OH:36])([CH3:35])[CH2:33][CH2:32][CH2:31][N:20]1[C:21](=[O:30])[C:22]2[N:23]([CH2:27][CH2:28][CH3:29])[CH:24]=[N:25][C:26]=2[N:18]([CH2:16][CH3:17])[C:19]1=[O:37])[CH2:14][CH3:15]
Reactant: CCCn1cnc2c1c(=O)n(CCCC(C)=O)c(=O)n2CC
Reactant: C#CCN(CCC)CCC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCN(CC#CC(C)(O)CCCn1c(=O)c2c(ncn2CCC)n(CC)c1=O)CCC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
5.3 ml (8.45 mmol) of a 15% strength butyllithium solution in n-hexane were slowly added dropwise to a solution of 1.36 ml (7.8 mmol) of N,N-dipropyl-2-propynylamine in 6 ml of tetrahydrofuran at -78° C., and the mixture was stirred at -78° C. for one hour. After warming to room temperature, a solution of 2.0 g (6.5 mmol) of 3-ethyl-1-(4-oxopentyl)-7-propylxanthine in 8 ml of tetrahydrofuran was added. After 7 hours at room temperature, the mixture was adjusted to pH 6-7 with 4 N hydrochloric acid and partitioned between 5% strength sodium bicarbonate solution and dichloromethane. The organic phase was dried with magnesium sulfate, concentrated under reduced pressure and purified by flash chromatography, dichloromethane/methanol=19/1.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(CC)CC.[CH3:13][C:14]1([CH3:22])[O:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][O:15]1>C(Cl)Cl>[CH3:13][C:14]1([CH3:22])[O:19][CH2:18][CH:17]([CH2:20][O:21][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:16][O:15]1
Reactant: CC1(C)OCC(CO)CO1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OCC(COS(C)(=O)=O)CO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
MsCl (4.4 mL, 56 mmol) was added slowly to a solution of Et3N (9.8 mL, 71 mmol) and (2,2-dimethyl-[1,3]dioxan-5-yl)-methanol (6.87 g, 47.0 mmol) in CH2Cl2 (100 mL) at 0° C. (bath temp). The reaction mixture was stirred at rt for 2 h and then quenched with H2O (100 mL). The mixture was extracted with CH2Cl2 and the organic fractions were dried (MgSO4) and concentrated in vacuo to give the title compound as a colorless liquid: yield 10.02 g (95%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[CH:14][N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=3[C:4]=2[CH:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:16]([N:15]1[C:5]2[C:4]3[CH:3]=[C:2]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:12])[C:6]=2[N:13]=[CH:14]1)[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Reactant: OB(O)c1ccccc1
Product: CC(C)Cn1cnc2c(N)nc3ccc(-c4ccccc4)cc3c21

Procedure:
8-Bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and benzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Recrystallization from isopropanol followed by recrystallization from methanol afforded 1-isobutyl-8-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as a beige solid, m.p. 203-204° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](F)[C:3]=1[C:13]([CH3:15])=[CH2:14].[CH3:16][S-:17].[Na+].CCOCC>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([S:17][CH3:16])[C:3]=1[C:13]([CH3:15])=[CH2:14]
Reactant: C[S-]
Reactant: C=C(C)c1c(Cl)ccc(C(=O)OC)c1F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=C(C)c1c(Cl)ccc(C(=O)OC)c1SC
Temperature: 50 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
A mixture of methyl 4-chloro-2-fluoro-3-isopropenylbenzoate (8.6 g) and sodium thiomethoxide (3.15 g) in dimethyl formamide was heated at 50° C. for 3 hours and stirred at room temperature overnight. Ether was added and the mixture was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography eluted with a mixture of ethyl acetate and hexane to give methyl 4-chloro-3-isopropenyl-2-(methylsulphenyl)benzoate (5.95 g) as a clear oil NMR (CDCl3) 2.1(s,3H), 2.35(s,3H), 3.95(s,3H), 4.9(s,1H), 5.4(s,1H), 7.45(s,2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[C:14]([C:15](=[O:17])[CH3:16])=[CH:13][CH:12]=[CH:11][N:10]=1.CCN(C(C)C)C(C)C.[Si:27](OS(C(F)(F)F)(=O)=O)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>C(Cl)Cl>[Si:27]([O:17][C:15]([C:14]1[C:9]([C:8]#[C:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:10][CH:11]=[CH:12][CH:13]=1)=[CH2:16])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(=O)c1cccnc1C#Cc1ccccn1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C(C)(C)C)c1cccnc1C#Cc1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
455 mg 1-(2-(pyridin-2-ylethynyl)pyridin-3-yl)ethanone was dissolved in 10 mL DCM, 1.069 mL of DIPEA was added, the solution was cooled 0° C. and 1.42 mL of tert-butyldimethylsilyltrifluormethansulfonate added slowly. The mixture was stirred 30 min at 0° C., warmed to 25° C. and filtrated over a plug of silica (cyclohexane/ethylacetate 1:1+small amount of TEA) to yield 1.025 g 3-(1-(tert-butyldimethylsilyloxy)vinyl)-2-(pyridin-2-ylethynyl)pyridine as oil. Analysis: HPLC-MS: Rt=1.59 min (method E) m+H=337.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]([C:58]1[CH:65]=[CH:64][CH:63]=[CH:62][C:59]=1[C:60]#[N:61])=[C:56]=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:56]([NH:55][C:58]2[CH:65]=[CH:64][CH:63]=[CH:62][C:59]=2[C:60]#[N:61])=[O:57])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: N#Cc1ccccc1N=C=O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1NC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 57 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-isocyanatobenzonitrile as starting materials in 57% yield. LCMS for C32H31ClN9O2 (M+H)+: m/z=608.2.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[C:8]([NH:10][C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:16][C:17]1[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:18]=1[C:19](Cl)=[O:20]>>[Cl:16][C:17]1[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:18]=1[C:19]([C:3]1[C:4]2[C:9](=[C:8]([NH:10][C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])[N:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:20]
Reactant: O=C(Cl)c1c(F)ccc(F)c1Cl
Reactant: O=C(Nc1cc2cc[nH]c2cn1)C1CC1
Product: O=C(c1c(F)ccc(F)c1Cl)c1c[nH]c2c(NC(=O)C3CC3)nccc12

Procedure:
N-[3-(2-Chloro-3,6-difluorobenzoyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]cyclopropanecarboxamide was prepared using N-(1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropane carboxamide and 2-chloro-3,6-difluorobenzoyl chloride (Compound No. 37).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:2].[H-].[Na+].Br[CH2:17][CH2:18]Br>CS(C)=O>[C:1]([C:3]1([C:4]2[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:18][CH2:17]1)#[N:2]
Reactant: COC(=O)c1cccc(CC#N)c1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1cccc(C2(C#N)CC2)c1
Yield: 75.1 %

Procedure:
Using methyl 3-(cyanomethyl)benzoate (1.5 g, 8.6 mmol), sodium hydride (60% in oil, 1.0 g, 26 mmol), 1,2-dibromoethane (2.4 g, 13 mmol) and dimethyl sulfoxide (30 mL) as starting materials and in the same manner as in Reference Example 31, the title compound (1.3 g, 76%) was obtained as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[C:8]([N:27]1[CH:31]=[C:30]([CH2:32][OH:33])[N:29]=[CH:28]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Si:34]([O:41][CH:42]([C:46]1[CH:51]=[CH:50][C:49]([C:52]#[N:53])=[CH:48][CH:47]=1)[C:43](O)=[O:44])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]>ClCCl>[Si:34]([O:41][CH:42]([C:46]1[CH:47]=[CH:48][C:49]([C:52]#[N:53])=[CH:50][CH:51]=1)[C:43]([O:33][CH2:32][C:30]1[N:29]=[CH:28][N:27]([C:8]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:31]=1)=[O:44])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)(C)[Si](C)(C)OC(C(=O)O)c1ccc(C#N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(C(=O)OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.0 mmol of triethylamine and 1.0 mmol propanephosphonic acid cyclic anhydride [68957-94-8](50% in ethyl acetate) are added to a solution of 1.0 mmol of (1-trityl-1H-imidazol-4-yl)methanol [33769-07-2] and 1.0 mmol of (tert-butyldimethylsilanyloxy)(4-cyanophenyl)acetic acid in 20 ml of dichloromethane. The reaction mixture is stirred at room temperature for 3 hours and diluted with dichloromethane. The phases are separated and the organic phase is washed with 1M HCl and brine, dried with sodium sulphate and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60F).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:23]([OH:25])=[O:24])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH2:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)[CH:6]=2.C(=O)([O-])O.[Na+].[C:31](OC(=O)C)(=[O:33])[CH3:32].Cl>O1CCCC1.O>[C:31]([N:13]([CH2:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([OH:1])[C:3]([C:23]([OH:25])=[O:24])=[CH:4]2)=[CH:9][CH:8]=1)[C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)c1ccc(NCc2ccc3cc(O)c(C(=O)O)cc3c2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N(Cc1ccc2cc(O)c(C(=O)O)cc2c1)c1ccc(C(C)C)cc1
Yield: 79.5 %

Procedure:
3-Hydroxy-7-[(4-(2-propyl)phenylamino)methyl]naphthalene-2-carboxylic acid (25 mg, 0.07 mmol) (example 363) was suspended in tetrahydrofuran (200 μL). A solution of sodium hydrogencarbonate (23 mg, 0.27 mmol) in water (200 μL) was added followed by acetic anhydride (14 μL, 15 mg, 0.15 mmol). The reaction mixture was stirred vigorously for 65 hours at room temperature before 6 N hydrochloric acid (4 mL) was added. The precipitate was filtered off and rinsed with water (3×1 mL) to yield the title compound (21 mg). No further purification was necessary.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[O:24])[N:14]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19][C:15]3=[N:16][C:17]=2[CH:18]=1.[F:25][C:26]([F:31])([F:30])[CH2:27][CH:28]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[O:24])[N:14]3[CH2:23][CH2:22][N:21]([CH2:28][CH2:27][C:26]([F:31])([F:30])[F:25])[CH2:20][CH2:19][C:15]3=[N:16][C:17]=2[CH:18]=1
Reactant: O=c1c2ccc(C#Cc3ccccn3)cc2nc2n1CCNCC2
Reactant: O=CCC(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=c1c2ccc(C#Cc3ccccn3)cc2nc2n1CCN(CCC(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8-(2-(pyridin-2-yl)ethynyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one (150 mg, 0.48 mmol), 3,3,3-trifluoropropanal (80 mg, 0.72 mmol), and sodium cyanoborohydride (60 mg, 0.96 mmol) in MeOH (10 mL) was added acetic acid (29 mg, 0.48 mmol). The mixture was stirred for 1 h at room temperature. The reaction mixture was quenched with saturated sodium carbonate solution (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the desired product. The product was then converted to the corresponding 2HCl salt. MS (ESI): 413 (MH+); 1H NMR (300 MHz, CD3OD) δ 8.94-8.92 (d, J=5.82 Hz, 1H), 8.72-8.66 (t, J=7.98 Hz, 1H), 8.39-8.34 (t, J=9.00 Hz, 2H), 8.15-8.10 (t, J=7.83 Hz, 1H), 8.07 (s, 1H), 7.91-7.88 (d, J=8.22 Hz, 1H), 4.84-4.80 (m, 3H), 3.81-3.71 (m, 5H), 3.66-3.54 (m, 2H), 3.03-2.94 (m, 2H). mGluR5 PAM EC50: ++. Fold shift at 10 μM: +++.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:11][C@@H:12]([C@H:14]2[CH2:18][N:17]([C@@H:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH3:20])[C:16](=[O:29])[CH2:15]2)[CH3:13])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[CH3:30][N:31]1[C:35]2[CH:36]=[C:37]([Sn](CCCC)(CCCC)CCCC)[S:38][C:34]=2[CH:33]=[N:32]1.[F-].[Cs+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([C@H:19]([N:17]2[CH2:18][C@H:14]([C@H:12]([O:11][C:4]3[C:5]4[N:6]([N:8]=[CH:9][CH:10]=4)[CH:7]=[C:2]([C:37]4[S:38][C:34]5[CH:33]=[N:32][N:31]([CH3:30])[C:35]=5[CH:36]=4)[CH:3]=3)[CH3:13])[CH2:15][C:16]2=[O:29])[CH3:20])=[CH:22][CH:23]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2c(cnn2C)s1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Br)cn4nccc34)CC2=O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(-c4cc5c(cnn5C)s4)cn4nccc34)CC2=O)cc1
Temperature: 50 °C

Procedure:
A solution of (R)-4-((R)-1-((6-bromopyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 6.01 (30 mg, 0.065 mmol) and 1-methyl-5-(tributylstannyl)-1H-thieno[3,2-c]pyrazole (36 mg, 0.085 mmol, prepared according to protocols described in WO2012/177714 and US2012/043276) were dissolved in DMF (0.6 mL). Cesium fluoride (20 mg, 0.13 mmol), cuprous iodide (2.5 mg, 0.013 mmol) and Pd(PPh3)4 (7.6 mg, 0.0066 mmol) were added. Argon gas was bubbled through the reaction mixture for 2 minutes and the reaction was heated to 50° C. for 16 h. The reaction was cooled to room temperature, EtOAc and water were added, the layers were separated and the aqueous layer was extracted with EtOAc (1x). The combined organics were washed with water, dried (MgSO4), filtered and concentrated to a residue which was purified by silica gel chromatography (0-5% MeOH in EtOAc) to afford (R)-1-((R)-1-(4-methoxyphenyl)ethyl)-4-((R)-1-((6-(1-methyl-1H-thieno[3,2-c]pyrazol-5-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 6.28.
Reaction SMILES: CO[C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3([CH3:19])[O:18]CCO3)[CH:12]=2)[N:7]([CH2:20][CH3:21])[C:6]1=[O:22])=[O:4].[NH2:23][C:24]1[CH:25]=[C:26]([CH:36]=[CH:37][CH:38]=1)[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:28]>>[CH:30]1([NH:29][C:27]([C:26]2[CH:25]=[C:24]([NH:23][C:3]([CH:5]3[C:13]4[C:8](=[CH:9][CH:10]=[C:11]([C:14](=[O:18])[CH3:19])[CH:12]=4)[N:7]([CH2:20][CH3:21])[C:6]3=[O:22])=[O:4])[CH:38]=[CH:37][CH:36]=2)=[O:28])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CCN1C(=O)C(C(=O)OC)c2cc(C3(C)OCCO3)ccc21
Reactant: Nc1cccc(C(=O)NC2CCCCC2)c1
Product: CCN1C(=O)C(C(=O)Nc2cccc(C(=O)NC3CCCCC3)c2)c2cc(C(C)=O)ccc21

Procedure:
Prepared as in Example 1 from 1-ethyl-5-(2-methyl-[1,3]dioxolan-2-yl)-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid methyl ester and 3-amino-N-cyclohexyl-benzamide. Purified by trituration in ethyl acetate. mp 180° C. dec.