Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20]CC3C=CC=CC=3)[CH:15]=2)[CH:10]([O:28][CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[CH:10]([O:28][CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COc2cccc(C3CCN(Cc4ccccc4)CC3OCc3ccc4ccccc4c3)c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: Oc1cccc(C2CCN(Cc3ccccc3)CC2OCc2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 31.5 %

Procedure:
A solution of 250 mg (0.487 mmol) of (3RS,4RS)-1-benzyl-4-(3-benzyloxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine in 1.1 ml of methylene chloride was treated at room temperature with 247 μl (236 mg, 1.946 mmol, 4 eq.) of N,N-dimethylaniline and 195 mg (1.46 mmol, 3.0 eq.) of aluminium trichloride and stirred at room temperature for 2.5 hours. Subsequently, the mixture was partitioned between methylene chloride and 5% sodium hydrogen carbonate solution, the organic phase was dried over magnesium sulphate and finally the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel with a 4:1 mixture of methylene chloride and hexane as the eluent. There were obtained 65 mg (32% of theory) of (3RS,4RS)-1-benzyl-4-(3-hydroxyphenyl)-3-(naphthalen-2-ylmethoxy)-piperidine as a beige coloured solid; MS: 423 (M)+.
Reaction SMILES: [C:1]1([CH:7]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=1)=[O:29]>C(#N)C>[Br-:26].[C:37]([NH:36][C:33]1[CH:34]=[CH:35][C:30]([C:28](=[O:29])[CH2:27][N+:13]23[CH2:14][CH2:15][CH:16]([CH2:17][CH2:18]2)[C@@H:11]([O:10][C:8](=[O:9])[C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12]3)=[CH:31][CH:32]=1)(=[O:39])[CH3:38]
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1ccccc1
Reactant: CC(=O)Nc1ccc(C(=O)CBr)cc1
Solvent: CC#N
Product: CC(=O)Nc1ccc(C(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)[C@H](Nc2ccccc2)c2ccccc2)C3)cc1
Product: [Br-]

Procedure:
A mixture (R)—((R)-quinuclidin-3-yl) 2-phenyl-2-(phenylamino)acetate (Diastereoisomer 1 of C2) (80.0 mg, 0.24 mmol) and N-(4-(2-bromoacetyl)phenyl)acetamide (60.9 mg, 0.24 mmol) in acetonitrile (2 mL) is heated in a microwave oven at 100° C. for 1 hour (UPLC-MS monitoring: complete conversion). The title compound is isolated by suction filtration and washed with Et2O (98.2 mg, 81% yield, off-white solid, bromide salt, single diastereoisomers).
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:15])([F:14])[C-:5]([C:10]([F:13])([F:12])[F:11])[C:6]([F:9])([F:8])[F:7].CN([S+](N(C)C)N(C)C)C.FC(F)(F)C(=C(F)F)C(F)(F)F.F[Si](C)(C)C>C(#N)C1C=CC=CC=1>[Br:1][C:5]([C:6]([F:9])([F:8])[F:7])([C:10]([F:11])([F:12])[F:13])[C:4]([F:14])([F:15])[F:3]
Reactant: FC(F)(F)[C-](C(F)(F)F)C(F)(F)F
Reactant: BrBr
Agent: CN(C)[S+](N(C)C)N(C)C
Agent: C[Si](C)(C)F
Agent: FC(F)=C(C(F)(F)F)C(F)(F)F
Solvent: N#Cc1ccccc1
Product: FC(F)(F)C(Br)(C(F)(F)F)C(F)(F)F
Yield: 81 %

Procedure:
Bromine, 17.25 g (0.108 mol), was added dropwise at 0° to a solution of tris(dimethylamino)sulfonium 1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)-2-propanide, prepared by dissolving 33.4 g (0.12 mol) of tri(dimethylamino)sulfonium difluorotrimethylsilicate and 24.0 g (0.12 mol) of perfluoroisobutylene in 75 mL of benzonitrile, then pumping out the by-product fluorotrimethylsilane at reduced pressure. The reaction mixture was evacuated to transfer the volatile reaction product into a cold trap (-78°). Sublimation of the contents of the trap at atmospheric pressure gave 26.11 g (81%) of 2-bromo-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane as a very volatile solid: m.p. (sublimation 49°-51°; 19F NMR (CDCl3) δ -67.6 ppm (s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]#[N:12].C(N(CC)CC)C.[CH2:24]([O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])O.[Na+]>CCOCC.O>[C:11]([C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:35](=[O:36])[C:34]1[CH:33]=[CH:32][C:31]([O:30][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:39][CH:38]=1)#[N:12]
Reactant: CCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: N#Cc1ccccc1Sc1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCOc1ccc(C(=O)Nc2ccccc2Sc2ccccc2C#N)cc1

Procedure:
In 2 ml of thionyl chloride was dissolved 1.03 g of 4-hexyloxybenzoic acid and the solution was refluxed for 1 hour. The excess thionyl chloride was distilled off and the residue was dried in vacuo to give 4-hexyloxybenzoyl chloride. Separately, 1.00 g of 2-(2-aminophenylthio)benzonitrile and 0.89 g of triethylamine were dissolved in 10 ml of ether and while the solution was stirred with ice-cooling, a solution of the above 4-hexyloxybenzoyl chloride in 5 ml of ether was added. The mixture was stirred overnight. Next morning, water and an aqueous solution of sodium hydrogen carbonate were added in the order mentioned and the resulting precipitate was extracted with ethyl acetate. The extract was dried over magnesium sulfate, the solvent was distilled off, and the residue was recrystallized from ethyl acetate-n-hexane to give 1.27 g of the title compound as white prisms.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH:27]([CH3:28])[C:26](=[O:29])[NH:25][C:24]4=[O:30])=[N:21][CH:22]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:31]I>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH:27]([CH3:28])[C:26](=[O:29])[N:25]([CH3:31])[C:24]4=[O:30])=[N:21][CH:22]=3)=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NC(=O)C4C)nc3)CC2)c(C)c1
Reactant: CI
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4C)nc3)CC2)c(C)c1

Procedure:
Using 1-{5-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}-5-methylimidazolidine-2,4-dione (50 mg) described in Example 516 and methyl iodide (9 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (23 mg) was obtained.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][CH2:4][CH:3]1[CH:9]([CH:11]([CH3:13])[CH3:12])[OH:10].C(O)(C)C.Cl.O>C1(C)C=CC=CC=1>[CH3:8][C:6]12[CH2:5][CH2:4][CH:3]([CH:2]([CH3:1])[CH2:7]1)[CH:9]([CH:11]([CH3:13])[CH3:12])[O:10]2
Reactant: CC1=CC(C)C(C(O)C(C)C)CC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: O
Product: CC(C)C1OC2(C)CCC1C(C)C2
Yield: 19.2 %

Procedure:
A solution of 130 grams of 2,4-dimethyl-alpha-isopropyl-3-cyclohexene methanol, 300 grams of isopropyl alcohol and 1000 ml of concentrated HCl is heated 21/2 hours at reflux. The reaction mass is cooled and 1500 ml of H2O and 100 ml of toluene is added with stirring. The aqueous layer is discarded and the organic layer is washed twice with water, neutralizing with aqueous caustic soda on the second wash. The organic layer is distilled through a 48" Vigreux column affording 25 grams of 1,5-dimethyl-3-isopropyl-2-oxabicyclo[2.2.2]octane (b.p. 55° C., 1.8 mm Hg pressure).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([OH:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1>C(Cl)(Cl)Cl>[Cl:3][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([OH:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: OCCCNC1=Nc2ccccc2C1(O)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: OC1(c2ccccc2)C(NCCCCl)=Nc2ccccc21
Temperature: 25 °C

Procedure:
Thionylchloride (1.53 ml.) was added dropwise to a stirred cooled suspension of 2-(3-hydroxypropylamino)-3-phenyl-3H-indol-3-ol (3 g.) in chloroform (25 ml.). On completion of the addition the reaction was allowed to warm to room temperature and then heated under reflux for 45 minutes. The solvent and excess thionyl chloride were removed under reduced pressure and the resulting product crystallised from isopropanol-ether to give the title compound as its hydrochloride salt (2.72 g.). After two recrystallisations from isopropanol-ether the hydrochloride had a m.p. 210°-212°C. (Found C, 60.8; H. 5.6; N, 8.3. C17H17ClN20HCl requires C, 60.5; H, 5.4; N 8.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.Cl[C:21]1C=CC(C(C2C=CC(Cl)=CC=2)CC(O)=O)=C[CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:9][C:10]([O:12][CH2:21][CH3:22])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=C(O)C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: CCOC(=O)CC(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
Prepared in a similar manner from 3,3-bis(p-chlorophenyl)acrylic acid was 3,3-bis(p-chlorophenyl)propionic acid, m.p. 190°-193° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[N:13]=[C:14]([NH:17][CH:18]4[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26].O>C(Cl)Cl>[C:25]([NH:29][C@H:21]1[CH2:22][CH2:23][C@H:18]([NH:17][C:14]2[CH:15]=[CH:16][C:11]3[N:12]([C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)=[CH:9][N:10]=3)[N:13]=2)[CH2:19][CH2:20]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C1CCC(Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Reactant: CC(C)(C)N
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of 4-((3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexanone (80 mg, 0.23 mmol) and t-Butylamine (17.2 mg, 0.23 mmol) in CH2Cl2 (1.2 mL) was added dropwise Ti(Oi-Pr)4 (0.27 mL, 0.92 mmol). The resulting mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The mixture was poured into water (150 mL) and extracted with EtOAc (100 mL*3). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep. HPLC to give EX. 8-78 (15 mg, 16.5%) as a white solid.
Reaction SMILES: C1(O[C:8](=[O:20])[NH:9][CH2:10][C:11]2[CH:19]=[CH:18][C:17]3[O:16][CH2:15][O:14][C:13]=3[CH:12]=2)C=CC=CC=1.Cl.[NH2:22][CH2:23][CH2:24][SH:25].[OH-].[Na+]>N1C=CC=CC=1>[SH:25][CH2:24][CH2:23][NH:22][C:8]([NH:9][CH2:10][C:11]1[CH:19]=[CH:18][C:17]2[O:16][CH2:15][O:14][C:13]=2[CH:12]=1)=[O:20]
Reactant: O=C(NCc1ccc2c(c1)OCO2)Oc1ccccc1
Reactant: NCCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: O=C(NCCS)NCc1ccc2c(c1)OCO2

Procedure:
6 g (0.022 mol) of phenylpiperonylcarbamate, prepared as in example 2A, are placed in pyridine and a heterogenous suspension is obtained. Separately a solution made in a nitrogen stream of 2.75 g (0.024 mol) of cysteamine hydrochloride and of NaOH (0.96 g, 0.024 mol) is prepared. The cysteamine solution thus obtained is added to the phenylpiperonylcarbamate solution and heated while stirring for 8 hours.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH:16]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)([CH3:18])[CH3:17]>>[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=2)=[CH:21][CH:20]=1)([CH3:18])[CH3:17]
Reactant: CCOC(=O)/C=C(\C)c1ccc(Br)cc1
Reactant: CC(C)c1ccc(B(O)O)cc1
Product: CCOC(=O)/C=C(\C)c1ccc(-c2ccc(C(C)C)cc2)cc1

Procedure:
The colourless solid, (E)-ethyl 3-(4′-isopropyl-biphenyl-4-yl)-but-2-enoate was prepared from (E)-ethyl 3-(4-bromophenyl)-but-2-enoate (example 50a) and 4-isopropylphenyl boronic acid by a procedure analogous to that described in example 52a.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:5]([S:8][CH:9]([F:11])[F:10])[C:6]=1[Br:7].ClC1C=C(C=CC=1)C(OO)=[O:24].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl.O>[Br:1][C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:5]([S:8]([CH:9]([F:11])[F:10])=[O:24])[C:6]=1[Br:7]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)Sc1c(-c2ccc(Cl)cc2)[nH]c(Br)c1Br
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=S(c1c(-c2ccc(Cl)cc2)[nH]c(Br)c1Br)C(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 522.9 %

Procedure:
A solution of 2,3-dibromo-5-(p-chlorophenyl)-4-[(difluoromethyl)thio]pyrrole (125 mg, 0.030 mmol) in chloroform is treated with 3-chloroperoxybenzoic acid (86 mg, 60%, 0.30 mmol) at 0° C. The reaction mixture is stirred for one hour at 0° C., warmed to room temperature, stirred overnight, poured into saturated sodium metabisulfite solution and diluted with a methylene chloride/water mixture. The organic phase is separated, washed with saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. Flash chromatography of the residue using silica gel and a 1:10 ethyl acetate/hexanes solution gives the title product as a yellow solid (68 mg, mp 180° C. (dec)) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[NH:9][C:10](=O)[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:3]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[C:8]([NH:7][C:4]2[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=2)[N:9]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(=O)[nH]2)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Temperature: 130 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
3-(5-Methyl-1H-pyrazol-3-ylamino)-2H-isoquinolin-1-one (7.4 g, 0.03 mol) and POCl3 (80 ml) were sealed in 4 bottles (20 ml). The mixture was heated at 130° C. for 15 minutes under microwave irradiation. The mixture was concentrated, and the residue was treated with 15 ml MeOH. The mixture was stirred for 2 hours at room temperature, and the solid was collected and dried to give desired product (4.7 g, 61% yield). LC-MS: 259 (MH+)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH:9]=O)=O)[CH:2]=1.C(=O)(O)O.[NH2:15][NH:16][C:17]([NH2:19])=[NH:18]>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:18]=[C:17]([NH2:19])[N:16]=[N:15][CH:9]=2)[CH:2]=1
Reactant: N=C(N)NN
Reactant: O=CC(=O)c1cccnc1
Agent: O=C(O)O
Solvent: CCO
Product: Nc1nncc(-c2cccnc2)n1
Yield: 39.4 %

Procedure:
5-(Pyridin-3-yl)-1,2,4-triazin-3-amine (1.5 g, 16% over 2 steps) was prepared from a crude sample of 3-pyridylglyoxal (10.0 g) and aminoguanidine hydrogen carbonate (3.0 g, 22 mmol). The reagents were refluxed in EtOH (100 mL) for 4 hours. The reaction mixture was then cooled, concentrated under reduced pressure and purified by gradient flash chromatography (eluting with 0-30% ethyl acetate/hexane).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[C:9]2[CH:16]=[CH:15][N:14]([C@H:17]([CH3:20])[CH2:18][OH:19])[C:10]=2[N:11]=[CH:12][N:13]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Cl:7][C:8]1[C:9]2[CH:16]=[CH:15][N:14]([C@H:17]([CH3:20])[CH2:18][O:19][CH:6]3[CH2:5][CH2:4][CH2:3][CH2:2][O:1]3)[C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: C[C@H](CO)n1ccc2c(Cl)ncnc21
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C[C@H](COC1CCCCO1)n1ccc2c(Cl)ncnc21
Yield: 100 %

Procedure:
2,3-Dihydropyran (25.0 mL, 270 mmol) was added to (2R)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-1-ol (11.00 g, 51.97 mmol) (see Preparation 3) and pyridinium toluene-4-sulphonate (3.92 g, 15.6 mmol) in DCM (150 mL). The reaction mixture was washed with water (200 mL) and the aqueous phase was extracted with DCM (2×150 mL). The combined organic phases were dried over magnesium sulfate and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of heptane:EtOAc 100:0 to 70:30) to afford the title compound as a yellow oil in 100% yield, 15.65 g.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C[Si]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(C)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)=O)=[CH:24][CH:23]=1>C1COCC1>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:26][CH:27]=1
Reactant: CCOC(=O)C[Si](C)(C)C
Reactant: O=C(c1ccc(O)cc1)c1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(c1ccc(O)cc1)c1ccc(F)cc1
Reaction time: 0.33 h
Yield: 53.3 %

Procedure:
A solution of lithium hexamethyldisilazide (23.1 mL, 1M in THF) was added to a stirred solution of ethyl (trimethylsilyl)acetate (2.53 mL, 13.9 mmol) in THF (15 mL) in 10 min. at −78° C. The reaction mixture was further stirred at this temperature for 20 min. A solution of (4-fluorophenyl)-(4-hydroxyphenyl)-methanone (2 g, 9.2 mmol) in THF (30 mL) was slowly added to the reaction mixture. The reaction mixture was brought to 0° C. in 5 h. The reaction mixture was quenched with saturated ammonium chloride solution, extracted into ethyl acetate and washed with dilute ammonium chloride solution. The organic layer was dried over magnesium sulfate. The solvent was removed under vacuum and product was purified flash chromatography on silica gel, giving 45.1 as an oil (1.405 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]5[N:31]=[CH:30][N:29](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[N:28]=5)[CH:25]=4)[N:20](C4CCCCO4)[N:19]=3)[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[NH:28]1[C:27]([C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[C:18]3[C:14]2[CH:13]=[C:12]([C:10]([NH:9][CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:11])[CH:17]=[CH:16][CH:15]=2)=[N:31][CH:30]=[N:29]1
Reactant: O=C(NCc1ccc(F)cc1)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NCc1ccc(F)cc1)c1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 50 °C
Yield: 30.6 %

Procedure:
To a stirred solution of N-[(4-fluorophenyl)methyl](3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl) (1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)carboxamide (0.423 g, 0.573 mmol) was added dioxane (4.0 mL) and aqueous 6 N hydrochloric acid (4.0 mL) and the mixture heated at 50° C. for 5.5 h. The mixture was cooled and poured into saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated. Addition of ethyl acetate (5 mL) initiated crystal growth and the ethyl acetate phase was pipetted off. The crystals were filtered. Purification by preparative HPLC (30-80% acetonitrile/water) followed by washing with saturated sodium bicarbonate and extraction with ethyl acetate gave the title compound (0.0723 g, 31% yield). 1H NMR (CD3OD) δ 8.78 (s, 1H), 8.49 (t, 1H), 8.22 (dt, 1H), 8.13 (d, 1H), 7.94 (dt, 1H), 7.70 (d, 1H), 7.68 (t, 1H), 7.43 (m, 2H), 7.07 (m, 2H), 4.60 (s, 2H). ES-MS (m/z) 413 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH2:18]([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]2[O:35][C:36]([C:39](Cl)=[O:40])=[CH:37][CH:38]=2)=[N:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH2:18]([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]2[O:35][C:36]([C:39](=[O:40])[NH:7][C:6]3[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=3)=[CH:37][CH:38]=2)=[N:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
0.29 g (1.8 mmol) of 4-trifluoromethylaniline were initially charged in 20 ml of THF1 0.14 g (1.8 mmol) of pyridine were added and a solution of 0.5 g (1.5 mmol) of 1-benzyl-3-(5-chlorocarbonyl-2-furyl)indazole in 10 ml of THF was added dropwise at RT. After 0.5 h, the mixture was poured into ice-water and the precipitate was filtered off with suction and recrystallized from isopropanol. This gave 0.47 g (69%) of the title compound. m.p.: 205-206° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C@@H:4](/[CH:5]=[C:6](/[F:12])\[C:7](=[O:11])[O:8]CC)[C@H:3]1[C:13]([O:15][C@H:16]([C:30]#[N:31])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:18]=1)=[O:14].O1CCOCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH3:1][C:2]1([CH3:32])[C@@H:4](/[CH:5]=[C:6](/[F:12])\[C:7](=[O:8])[OH:11])[C@H:3]1[C:13]([O:15][C@H:16]([C:30]#[N:31])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:18]=1)=[O:14]
Reactant: CCOC(=O)/C(F)=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C(/F)C(=O)O
Temperature: 25 °C
Yield: 41.9 %

Procedure:
A solution of 2.5 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(E)-[2-fluoro-3-oxo-3-ethoxy-propenyl]-cyclopropane-1-carboxylate, 10 ml of dioxane, 2.5 ml of water and 1 g of p-toluene sulfonic acid manohydrate was refluxed for 24 hours and then allowed to cool to room temperature. Methylene chloride was added to the mixture and the organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 60-40-1 cyclohexane-ethyl acetate-acetic acid mixture to obtain 980 mg of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(E)-[2-fluoro-3-oxo-3-hydroxy-propenyl]-cyclopropane-1-carboxylate.
Reaction SMILES: I[CH2:2][CH2:3][CH3:4].[CH:5]1([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([N:17]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[CH:24]=4)[N:19]=[CH:18]3)[CH:11]=2)[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[CH:5]1([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([N:17]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([N:28]5[CH2:29][CH2:30][N:31]([CH2:2][CH2:3][CH3:4])[CH2:32][CH2:33]5)[CH:24]=4)[N:19]=[CH:18]3)[CH:11]=2)[CH2:7][CH2:6]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(N3CCNCC3)cc2c1=O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCN1CCN(c2ccc3ncn(-c4cc(C(=O)NC5CC5)ccc4C)c(=O)c3c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Iodopropane (0.039 ml) was added to a stirred mixture of N-cyclopropyl-4-methyl-3-(4-oxo-6-piperazin-1-ylquinazolin-3(4H)-yl)benzamide (0.145 g) and potassium carbonate (0.199 g) in DMA (0.50 ml). The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (20 ml), the resulting solid was filtered and dried (magnesium sulphate) under vacuum at 40° C. There was thus obtained the title compound (0.109 g); NMR Spectrum: (DMSOd6) 0.54 (m, 2H), 0.68 (m, 2H), 0.87 (t, 3H), 1.48 (m, 2H), 2.12 (s, 3H), 2.28 (t, 2H), 2.50 (m, 4H), 2.84 (m, 1H), 3.27 (m, 4H), 7.45 (s, 1M), 7.50 (d, 1H), 7.62 (s, 2H), 7.80 (s, 1H), 7.87 (d, 1H), 8.06 (s, 1H), 8.41 (d, 1H); Mass Spectrum: M+H+ 446.