Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:29])[C:4]2([CH2:9][CH2:8][N:7]([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19](C(O)=O)[CH2:18][CH2:17]4)=[N:14][CH:15]=3)[CH2:6][CH2:5]2)[CH2:3]1.Cl>ClCCl.O1CCOCC1>[F:29][C:2]1([F:1])[C:4]2([CH2:9][CH2:8][N:7]([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[NH:19][CH2:18][CH2:17]4)=[N:14][CH:15]=3)[CH2:6][CH2:5]2)[CH2:3]1
Reactant: O=C(O)N1CCN(c2ccc(N3CCC4(CC3)CC4(F)F)cn2)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: FC1(F)CC12CCN(c1ccc(N3CCNc4ccccc43)nc1)CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.48 g of tert-butyl ester of 4-[5-(1,1-difluoro-6-aza-spiro[2.5]oct-6-yl)-pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid is put in 16 mL of dichloromethane. 24 mL of 4M hydrochloric acid in dioxane is added at +4° C. The solution is stirred at room temperature for 4 h and evaporated to dryness. The residue is taken up in a saturated solution of sodium hydrogen carbonate to basic pH. The solution is extracted twice with dichloromethane, washed with water, dried over magnesium sulfate, filtered and evaporated to dryness. 1.4 g of 1-[5-(1,1-difluoro-6-aza-spiro[2.5]oct-6-yl)-pyridin-2-yl]-1,2,3,4-tetrahydroquinoxaline is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:13]([CH2:14][NH:15][C:16]3[N:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=3)[CH2:12][N:11]([C:26]([CH:28]3[CH2:33][CH2:32][N:31]([C:34]([C:36]4([CH3:39])[CH2:38][CH2:37]4)=[O:35])[CH2:30][CH2:29]3)=[O:27])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].[CH3:42]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:13]([CH2:14][N:15]([CH3:42])[C:16]3[N:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:18][N:17]=3)[CH2:12][N:11]([C:26]([CH:28]3[CH2:29][CH2:30][N:31]([C:34]([C:36]4([CH3:39])[CH2:37][CH2:38]4)=[O:35])[CH2:32][CH2:33]3)=[O:27])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1(C(=O)N2CCC(C(=O)N3C[C@H](CNc4ncc(C(F)(F)F)cn4)[C@@H](c4ccc(Cl)c(Cl)c4)C3)CC2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1)c1ncc(C(F)(F)F)cn1
Yield: 62.2 %

Procedure:
{(3S,4S)-3-(3,4-Dichloro-phenyl)-4-[(5-trifluoromethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone (30.0 mg, 0.051 mmol) were dissolved in DMF (1 mL) and treated with NaH (55% dispersion in oil) (2.5 mg, 0.056 mmol) at ambient temperature. After 5 min methyl iodide (3.5 μL, 0.056 mmol) were added and the reaction mixture was stirred over night. After quenching with water and extraction with ethyl acetate (3×10 mL) the combined organic phases were dried on sodium sulfate and filtered. After evaporation of the solvent the crude product was subjected to column chromatography (silica gel, ethyl acetate) to yield the title product (19 mg, 62%) as a colorless foam. ES-MS m/e: 598.3 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:6][C:5]=1[C:15]([O:17]C)=[O:16])[CH3:2].[OH-].[K+]>O1CCCC1.O>[CH2:1]([O:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:6][C:5]=1[C:15]([OH:17])=[O:16])[CH3:2]
Reactant: CCOc1cc(-c2ccccc2)sc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(-c2ccccc2)sc1C(=O)O
Yield: 92.8 %

Procedure:
A solution of methyl 3-ethoxy-5-phenyl-2-thiophenecarboxylate (12.0 g, 46 mmoles) in tetrahydrofuran (150 mL) is added to a solution of potassium hydroxide (14.6 g, 229 mmoles) in water (150 mL). The mixture is stirred and heated under reflux for 24 hours, then the tetrahydrofuran is removed using a rotary evaporator. The aqueous suspension is cooled in an ice bath and acidified with concentrated HCl. The precipitate is collected by filtration, rinsed well with water and dried to afford the pure product (10.6 g); mp 174°-175° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:8]=1)[CH2:3][NH2:4].Br[C:21]1[S:25][C:24]([NH2:26])=[N:23][N:22]=1>>[CH3:1][CH:2]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:8]=1)[CH2:3][NH:4][C:21]1[S:25][C:24]([NH2:26])=[N:23][N:22]=1
Reactant: CC(CN)COc1cccc(CN2CCCCC2)c1
Reactant: Nc1nnc(Br)s1
Product: CC(CNc1nnc(N)s1)COc1cccc(CN2CCCCC2)c1

Procedure:
The compound is prepared by a method analogous to Example 51 from 2-methyl-3-[3-(1-piperidinylmethyl) phenoxy]-1-propanamine and 5-bromo-1,3,4-thiadiazole-2-amine.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]([C:15]2([C:18]3[CH:28]=[CH:27][C:21]4[O:22][C:23]([F:26])([F:25])[O:24][C:20]=4[CH:19]=3)[CH2:17][CH2:16]2)=[O:14])[N:3]=1.[OH:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[F:25][C:23]1([F:26])[O:22][C:21]2[CH:27]=[CH:28][C:18]([C:15]3([C:13]([NH:12][C:4]4[N:3]=[C:2]([C:34]5[CH:35]=[CH:36][C:31]([CH2:30][OH:29])=[CH:32][CH:33]=5)[C:11]5[C:6]([CH:5]=4)=[CH:7][CH:8]=[CH:9][CH:10]=5)=[O:14])[CH2:17][CH2:16]3)=[CH:19][C:20]=2[O:24]1
Reactant: O=C(Nc1cc2ccccc2c(Br)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: OCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Nc1cc2ccccc2c(-c2ccc(CO)cc2)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
N-(1-Bromoisoquinolin-3-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (45 mg, 0.10 mmol), 4-(hydroxymethyl)phenylboronic acid (23 mg, 0.15 mmol), and Pd(PPh3)4 (6 mg, 0.005 mmol) were combined in a reaction tube. DME (1 mL) and saturated Na2CO3 aqueous solution (100 μL) were added and the reaction vial was stirred under N2 atmosphere at 80° C. overnight. The mixture was filtered and concentrated. The residue was dissolved in DMSO and purified by reverse-phase HPLC to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(4-(hydroxymethyl)phenyl)isoquinolin-3-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 474.1. found 475.3 (M+1)+. Retention time 2.02 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.41 (s, 1H), 8.00-7.96 (m, 1H), 7.88-7.84 (m, 1H), 7.72 (t, J=7.1 Hz, 1H), 7.64-7.38 (m, 8H), 5.54 (s, 1H), 4.61 (s, 2H), 1.58-1.55 (m, 2H), 1.22-1.20 (m, 2H).
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](Cl)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.C(N(CC)CC)C.[Br:25][C:26]1[N:31]=[C:30]([NH2:32])[CH:29]=[CH:28][C:27]=1[Cl:33]>ClCCl>[Br:25][C:26]1[N:31]=[C:30]([NH:32][C:14]([C:11]2([C:9]3[CH:8]=[CH:7][C:5]4[O:6][C:2]([F:17])([F:1])[O:3][C:4]=4[CH:10]=3)[CH2:13][CH2:12]2)=[O:15])[CH:29]=[CH:28][C:27]=1[Cl:33]
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: Nc1ccc(Cl)c(Br)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)c(Br)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reaction time: 16 h
Yield: 69.4 %

Procedure:
1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (0.878 g, 3.37 mmol) was placed in an oven-dried flask which was allowed to cool under nitrogen. Dichloromethane (10 mL), triethylamine (1.42 mL, 10.1 mmol) and 6-bromo-5-chloropyridin-2-amine (10.1 mmol) were added and the reaction mixture was stirred for 16 hours. The reaction mixture was then washed with a saturated aqueous solution of sodium chloride, evaporated to near dryness, and then purified on 40 g of silica gel utilizing a gradient of 0-30% ethyl acetate in hexanes to yield N-(6-bromo-5-chloropyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (1.01 g, 69%). ESI-MS m/z calc. 429.9. found; 431.3 (M+1)+ Retention time 2.33 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:3]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: Clc1ccnc2ccccc12
Product: FC(F)(F)c1ccc(-c2cc(Cl)c3ccccc3n2)cc1

Procedure:
The title compound, m. p. 53-55° C., MS: m/e=307 (M+), was prepared from 4-chloro-quinoline and 4-bromo-benzotrifluoride.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:20])[CH:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8](OCC)=O)[CH3:4]>C(O)C>[CH2:8]=[C:7]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:6]([O:5][CH2:3][CH3:4])=[O:20]
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=C(Cc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
A mixture of of KOH (8.5 g) in ethanol (100 mL) was added at room temperature to benzylmalonic acid diethyl ester (40 g) in ethanol (80 mL) and the solution was stirred at room temperature overnight, then concentrated by evaporation. Water (14 mL) was added and then the mixture was acidified in an ice bath with concentrated hydrochloric acid (12.6 mL). The mixture was partitioned between water and ether; the organic phase was separated, dried and the ether was evaporated. The residue was treated with pyridine (26 mL), piperidine (1.22 g) and paraformaldehyde (3.56 g). The mixture was heated in an oil bath (130°) for 90 minutes, then cooled, and water (440 mL) was added. The mixture was extracted 3 times with n-hexane (150 mL). The combined organic phases were washed successively with water, 1N HCl, water, saturated NaHCO3 solution and brine. The organic solution was dried (MgSO4) and evaporated to give the title compound as colorless oil (26 g, 85% yield). 1H NMR: 300 MHz spectrum consistent with proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[N:13][CH:12]=1.Br[C:18]1[N:22]2[N:23]=[CH:24][C:25]([C:27]([OH:30])([CH3:29])[CH3:28])=[N:26][C:21]2=[N:20][CH:19]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[N:22]3[N:23]=[CH:24][C:25]([C:27]([OH:30])([CH3:28])[CH3:29])=[N:26][C:21]3=[N:20][CH:19]=2)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[N:13][CH:12]=1
Reactant: OB(O)c1ccc(F)c(-c2ccnnc2)c1
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Product: CC(C)(O)c1cnn2c(-c3ccc(F)c(-c4ccnnc4)c3)cnc2n1

Procedure:
4-Fluoro-3-(pyridazin-4-yl)phenylboronic acid (300 mg, 1.38 mmol) was coupled to 2-(7-bromoimidazo[1,2-b][1,2,4]triazin-3-yl)propan-2-ol (100 mg, 0.39 mmol) using the method of Example 20. Purification by chromatography (silica gel, 3% MeOH/CH2Cl2) then dissolving in toluene and washing with water followed by recrystallisation from hot toluene with isohexane gave the title compound as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 1.73 (6H, s), 3.23 (1H, s), 7.41 (1H, dd, J 10, 9 Hz), 7.75-7.78 (1H, m), 8.08-8.13 (1H, m), 8.28 (1H, s), 8.31 (1H, dd, J 7, 2 Hz), 8.83 (1H, s), 9.32 (1H, dd, J 5, 1 Hz), 9.50-9.52 (1H, m); MS (ES+) m/z 351 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:18]([NH2:21])[CH:19]=[CH2:20].C(=O)([O-])O.[Na+]>>[CH2:18]([NH:21][C:2]1[N:3]=[C:4]([NH:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:19]=[CH2:20]
Reactant: C=CCN
Reactant: Cc1csc2c(NC(CO)CO)nc(Cl)nc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NC(CO)CO)c2scc(C)c2n1
Yield: 82.9 %

Procedure:
In a sealed tube were heated 328 mg (1.2 mmol) of 2-chloro-4-(1,3-dihydroxypropan-2-yl)amino-7-methylthieno[3,2-d]pyrimidine and 1.10 g (19.2 mmol) of allylamine at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate (50 ml×2). The organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane =1/1) to give 293 mg (yield: 83.2%) of the title compound.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:10]([OH:21])([C:16]([O:18]CC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:22]([C@@H:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26])=[C:23]=[O:24]>C1COCC1>[CH2:3]([C:10]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:21][C:23](=[O:24])[N:22]([C@@H:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])[C:16]1=[O:18])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(O)(Cc1ccccc1)C(=O)OCC
Reactant: C[C@@H](N=C=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccccc2)OC(=O)N([C@H](C)c2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a mixture of NaOH (25 g) and 15.7 g of activated molecular sieves in 1159 mL of THF at 0° C. was added a 1159 mL THF solution of diethyl benzyl(hydroxy)propanedioate (153 g). After 5 min, to this mixture was added [(1R)-1-isocyanatoethyl]benzene (118 g). The mixture was stirred at 0° C. for 30 min and then warmed to ambient temperature and stirred for 4 h. The reaction mixture was directly purified using a Biotage silica gel chromatography system (5-30% ethyl acetate in hexanes) to give the title compound.
Reaction SMILES: COC1C=CC(C[O:8][C@H:9]([C@H:58]([CH3:71])[CH2:59][C@@H:60]([CH3:70])[CH2:61][O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[C@@H:10]([CH3:57])/[CH:11]=[CH:12]\[C@@H:13]([O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])[CH2:14][C@H:15]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[C@@H:16]([CH3:40])/[CH:17]=[CH:18]/[CH2:19][O:20][C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=CC=1.C(Cl)Cl.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O>[Si:63]([O:62][CH2:61][C@H:60]([CH3:70])[CH2:59][C@@H:58]([CH3:71])[C@@H:9]([OH:8])[C@@H:10]([CH3:57])/[CH:11]=[CH:12]\[C@@H:13]([O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:51])[CH3:52])[CH2:14][C@H:15]([O:41][Si:42]([C:45]([CH3:46])([CH3:47])[CH3:48])([CH3:44])[CH3:43])[C@@H:16]([CH3:40])/[CH:17]=[CH:18]/[CH2:19][O:20][C:21]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:66]([CH3:69])([CH3:67])[CH3:68])([CH3:65])[CH3:64]
Reactant: COc1ccc(CO[C@H]([C@H](C)C[C@@H](C)CO[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C/COC(c2ccccc2)(c2ccccc2)c2ccccc2)O[Si](C)(C)C(C)(C)C)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@@H](C)[C@@H](O)[C@@H](C)/C=C\[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1)O[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
The above PMB alcohol 85 (2.90 g, 2.77 mmol) was added to CH2Cl2 (25 mL) and H2O (1 mL), and DDQ (0.94 g, 4.15 μmol) was added. After 1 h of stirring, the reaction mixture was quenched by adding sat'd NaHCO3 (200 mL). The organic phase was washed by sat'd NaHCO3 solution (3×100 mL) and brine, dried over MgSO4 and concentrated. Purification by flash column chromatography (EtOAc/hexane 5:95) furnished 86 (2.16 g, 84%) as a colorless oil: IR (CHCl3) 3477, 2956, 2928, 2856, 1471, 1386, 1254, 1088, 836, 774 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.55-7.52 (m, 6H), 7.38-7.25 (m, 9H), 5.92 (dd, J=15.7, 6.0 Hz, 1H), 5.62 (dt, J=15.7, 5.5 Hz, 1H), 5.52 (dd, J=11.1, 9.3 Hz, 1H), 5.35 (t, J=10.5 Hz, 1H), 4.63 (m, 1H), 3.97 (m, 1H), 3.63 (d, J=5.4 Hz, 2H), 3.51-3.36 (m, 2H), 3.18 (m, 1H), 2.68 (m, 1H), 2.47 (m, 1H), 1.71-1.59 (m, 3H), 1.42-1.27 (m, 2H), 1.17 (m, 1H), 1.08 (d, J=6.7 Hz, 3H), 1.04 (d, J=6.9 Hz, 3H), 0.99 (s, 9H), 0.97 (s, 9H), 0.96 (s, 9H), 0.91 (d, J=6.8 Hz, 3H), 0.84 (d, J=6.6 Hz, 3H), 0.18 (s, 3H), 0.16 (s, 3H), 0.15 (s, 3H), 0.13 (s, 3H), 0.12 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 144.4, 135.2, 134.1, 131.1, 128.7, 127.7, 126.8, 126.4, 86.7, 79.8, 72.8, 69.6, 66.2, 65.2, 43.0, 42.1, 35.5, 33.7, 32.8, 32.5, 26.1, 26.0, 25.9, 18.4, 18.1, 17.6, 16.8, 16.3, 14.7, −2.9, −4.0, −4.15, −4.22, −5.3; LRMS (ESI) 951.7 [M+Na]+, 823.7, 577.4, 413.3, 328.4, 243.1; HRMS (ESI) calcd for C56H92O5Si3Na 951.6150 [M+Na]+, found 951.6165; [α]20D30.0 (c 3.6, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[N:14][C:15]([C:17](=O)[CH3:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)=[CH:5][CH:4]=1.CC([O-])=O.[Na+].Cl.[NH2:28][OH:29]>CO>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[N:14][C:15]([C:17](=[N:28][OH:29])[CH3:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(Cn2cnc3cc(C(C)=O)ncc32)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cn2cnc3cc(C(C)=NO)ncc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
To a mixture of 1-(3-(4-methoxybenzyl)-3H-imidazo[4,5-c]pyridin-6-yl)ethanone (500 mg, 1.78 mmol) and NaOAc (1.21 g, 17.80 mmol) in MeOH (10 mL) at RT was added hydroxylamine hydrochloride (618 mg, 8.90 mmol). The reaction was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure. To the residue was added water (100 mL) followed by extraction with EtOAc (50 mL×3). The combined extracts were dried (MgSO4), filtered and concentrated under reduced pressure to afford 320 mg (61%) of 1-(3-(4-methoxybenzyl)-3H-imidazo[4,5-c]pyridin-6-yl)ethanone oxime as a yellow solid. MS (ESI): m/z=297.2 [M+1]+.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[Cl:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[ClH:15].[Cl:15][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:8]=1[S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[NH:14][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: Nc1ccc(Sc2ccccc2)c(Cl)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(Sc4ccccc4)c(Cl)c3)c2cc1OC
Yield: 71 %

Procedure:
Using an analogous procedure to that described in Example 1 except that the reaction mixture was heated to reflux for 16 hours, 4-amino-2-chlorophenyl phenyl sulphide was reacted with 4-chloro-6,7-dimethoxyquinazoline hydrochloride to give 4-(3-chloro-4-phenylthioanilino)-6,7-dimethoxyquinazoline hydrochloride salt in 71% yield, m.p. 245°-247° C.;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:46]=[CH:45][C:6]([C:7]([O:22][CH2:23][C@@H:24]([OH:44])[C@@H:25]([OH:43])[C@@H:26]([O:39][CH2:40][CH2:41][F:42])[C@H:27]([N:30]2[CH:38]=[C:36]([CH3:37])[C:34](=[O:35])[NH:33][C:31]2=[O:32])[CH2:28][OH:29])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.N1C=CN=C1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.Cl[Si:67]([CH2:72][CH3:73])([CH2:70][CH3:71])[CH2:68][CH3:69]>CN(C=O)C.CCOC(C)=O>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([O:22][CH2:23][C@@H:24]([OH:44])[C@@H:25]([O:43][Si:67]([CH2:72][CH3:73])([CH2:70][CH3:71])[CH2:68][CH3:69])[C@@H:26]([O:39][CH2:40][CH2:41][F:42])[C@H:27]([N:30]2[CH:38]=[C:36]([CH3:37])[C:34](=[O:35])[NH:33][C:31]2=[O:32])[CH2:28][OH:29])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]2[CH:45]=[CH:46][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: COc1ccc(C(OC[C@@H](O)[C@@H](O)[C@@H](OCCF)[C@@H](CO)n2cc(C)c(=O)[nH]c2=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)O[C@@H]([C@@H](OCCF)[C@@H](CO)n1cc(C)c(=O)[nH]c1=O)[C@H](O)COC(c1ccccc1)(c1ccc(OC)cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.5 %

Procedure:
Compound 6, prepared as per the procedures illustrated in Example 13 (2.50 g, 4.00 mmol) was mixed with imidazole (1.36 g, 20.0 mmol) over P2O5 under reduced pressure. This mixture was dissolved in anhydrous DMF (13 mL) and chloro triethylsilane (1.71 mL, 10 mmol) was added. The mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted in EtOAc (100 mL), washed with sat. NaHCO3 (100 mL) and brine (50 mL) then dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by silica gel column chromatography (50% EtOAc in hexanes) to yield Compound 8 (2.45 g, 82.5%) as a white foam. MS (ES): m/z 760.2 [M+Na]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.Cl.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](Cl)=[O:20].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([NH:11][C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)=[O:20])[CH:3]=1
Reactant: Nc1cc(Br)cc2[nH]ncc12
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cc(Br)cc2[nH]ncc12)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-bromo-1H-indazol-4-amine (available from Sinova, 100 mg, 0.47 mmol), 2-pyridinecarbonyl chloride hydrochloride (available from Apollo, 100 mg, 0.71 mmol), DIPEA (0.164 ml) in DCM (10 ml) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. Purification by Mass Directed Automated Preparative HPLC (Method B) gave after evaporation of solvents the title compound (38 mg) as a white solid. LCMS (Method B) Rt=0.97 mins, MH+=318.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:33](=[O:34])[C:32]2[CH:36]=[CH:37][CH:38]=[C:30]([F:29])[CH:31]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: O=C(Cl)c1cccc(F)c1
Product: O=C1OC2(CCN(C(=O)c3cn(C(=O)c4cccc(F)c4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure VII as described above, the acylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with commercially available 3-fluorobenzoyl chloride gave the title compound. ES-MS m/e (%): 521.4 (M+H+).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][OH:5].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([NH:14][C:3](=[O:2])[CH2:4][OH:5])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)CO
Product: O=C(CO)NCc1ccccc1
Reaction time: 8 h

Procedure:
The procedure of 84A was followed with methyl2-hydroxyethanoate (8 g) and benzylamine (10 ml in 30 ml H2O). After one hour material precipitated out of solution. The mixture was stirred overnight, and the solid recovered by filtration to provide 4.12 g of white solid. The solvent was removed from the filtrate by vacuum to provide 4.71 g of material The solid and filtrate were combined and passed over a silica column eluting with a gradient of ethyl acetate to ethyl acetate/methanol (v:v, 1:1). Removal of solvent provided 8 g of white crystal product.