Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[N:5]([CH2:6][CH2:7][CH2:8][OH:9])[C:4](=[O:10])[CH:3]=[CH:2]1.[C:12]1(=[O:18])[O:17][C:15](=[O:16])[CH:14]=[CH:13]1.[CH:19]12[CH2:25][CH:22]([CH:23]=[CH:24]1)[CH2:21][CH:20]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C([C:35]12[CH2:41][CH:38]([CH:39]=[CH:40]1)[CH2:37][CH:36]2[C:42]([O:44]O)=[O:43])C.[CH:46]12[CH2:52][CH:49]([CH:50]=[CH:51]1)[CH2:48][CH:47]2[C:53]([OH:55])=[O:54].CC(N=NC(C#N)(C)C)(C#N)C>C1COCC1>[C:1]1(=[O:11])[N:5]([CH2:6][CH2:7][CH2:8][OH:9])[C:4](=[O:10])[CH:3]=[CH:2]1.[C:15]1(=[O:16])[O:17][C:12](=[O:18])[CH:13]=[CH:14]1.[C:29]([O:28][C:26]([CH:20]1[CH2:21][CH:22]2[CH2:25][CH:19]1[CH:24]=[CH:23]2)=[O:27])([CH3:32])([CH3:30])[CH3:31].[CH:35]12[CH2:41][CH:38]([CH:39]=[CH:40]1)[CH2:37][CH:36]2[C:42]([O:44][CH2:47][CH2:53][OH:54])=[O:43].[CH:46]12[CH2:52][CH:49]([CH:50]=[CH:51]1)[CH2:48][CH:47]2[C:53]([OH:55])=[O:54]
Reactant: CCC12C=CC(CC1C(=O)OO)C2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CC(C)(C)OC(=O)C1CC2C=CC1C2
Agent: O=C(O)C1CC2C=CC1C2
Solvent: C1CCOC1
Product: O=C(OCCO)C1CC2C=CC1C2

Procedure:
3-Maleimidylpropanol (13) (0.3 to 1 mol), 0.05 to 1 mol of maleic anhydride, 0.1 to 1 mol of t-butyl 5-norbornene-2-carboxylate (19), 0.05 to 1 mol of 2-hydroxyethyl 5-norbornene-2-carboxylate (21), and 0.01 to 0.3 mol of 5-norbornene-2-carboxylic acid (20) were dissolved in 150 to 250 g of THF to which was added 0.5 to 20 g of AIBN as a polymerization initiator. The reaction mixture was allowed to react at 60° C. to 75° C. for 4 to 24 hours under an argon atmosphere. The resulting crude resin was precipitated with hexane and dried to obtain poly[3-maleimidylpropanol/maleic anhydride/t-butyl-5-norbornene-2- carboxylate/2-hydroxyethyl 5- norbornene-2-carboxylate/5-norbornene-2-carboxylic acid] copolymer resin.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3[CH:18]=[C:19]([Cl:26])[C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:16]=3[N:15]=[C:14]2[C:27]([N:30]=[N+]=[N-])([CH3:29])[CH3:28])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17]3[CH:18]=[C:19]([Cl:26])[C:20]([C:22]([F:24])([F:25])[F:23])=[CH:21][C:16]=3[N:15]=[C:14]2[C:27]([NH2:30])([CH3:29])[CH3:28])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1ccc(-n2c(C(C)(C)N=[N+]=[N-])nc3cc(C(F)(F)F)c(Cl)cc32)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: CC(=O)OCCc1ccc(-n2c(C(C)(C)N)nc3cc(C(F)(F)F)c(Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.2 %

Procedure:
A mixture of 2-{4-[2-(1-azido-1-methylethyl)-6-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl acetate (step 2, 133 mg, 0.28 mmol) and Lindlar catalyst (13 mg) in methanol (5 ml) was stirred under H2 atmosphere at room temperature for 2.5 h. The catalyst was removed by filtration through a pad of celite and the filtrates were concentrated to give the title compound as yellow oil (121 mg, 98%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([CH2:22][CH2:23][CH3:24])=[C:20]([C:25]([OH:27])=O)[N:19]=[N:18]2)=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C[C:31]2N(O)N=[N:34][C:32]=2[CH:33]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH2:1]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([CH2:22][CH2:23][CH3:24])=[C:20]([C:25]([NH:34][CH:32]3[CH2:33][CH2:31]3)=[O:27])[N:19]=[N:18]2)=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: CCCc1c(C(=O)O)nnn1-c1ccc(C(=O)NCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(C(=O)NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 185.3 %

Procedure:
1-{4-[(Benzylamino)carbonyl]phenyl}-5-propyl-1H-1,2,3-triazole-4-carboxylic acid (507 mg, 1.39 mmol) obtained in Example 58b), HOBt (95 mg, 0.696 mmol, 0.5 eq.) and cyclopropylamine (0.129 ml, 1.81 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 9.0 ml), WSC (327 mg, 1.67 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (40 ml), and washed with 5% aqueous sodium hydrogen carbonate solution, 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane (1:1, 30 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and diethyl ether was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (520 mg, 1.29 mmol, 92.7%).
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)(Cl)=O.[N:11]1([C:17]2[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C([O-])(=O)C.[Na+]>O>[OH:23][C:19]1[CH:18]=[C:17]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH:22]=[CH:21][C:20]=1[CH:4]=[O:5]
Reactant: Oc1cccc(N2CCOCC2)c1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(N2CCOCC2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
DMF (10 mL) was treated dropwise with phosphorus oxychloride (2.3 g, 15 mmol). The reaction was kept at 25° C. by cooling on ice. The reaction mixture was treated with 3-(4-morpholinyl)phenol (2.5 g, 14 mmol) in small portions, stirred for 30 min at room temperature, then stirred at 100° C. for 8 h. After cooling, the mixture was poured into aqueous sodium acetate (1 M, 40 mL) and 10 mL of water was added. The resulting precipitate was collected by filtration, washed with water (10 mL), air dried, and purified by flash chromatography (silica gel, 4×7.5 cm, eluted with 90/10 CHCl3/ether) to yield the product as a light gray solid (0.66 g, 23%). See U.S. Pat. No. 4,147,552.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[CH3:20])[CH2:3][CH2:2]1.[NH2:21][C@@H:22]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23]([NH2:25])=[O:24]>>[C:23]([C@@H:22]([NH:21][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[CH3:20])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:26][CH:27]([CH3:29])[CH3:28])(=[O:24])[NH2:25]
Reactant: CC1CCCN1c1ccc(C(=O)O)nc1OCC1CC1
Reactant: CC(C)C[C@H](N)C(N)=O
Product: CC(C)C[C@H](NC(=O)c1ccc(N2CCCC2C)c(OCC2CC2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(2-methyl-pyrrolidin-1-yl)-pyridine-2-carboxylic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (LC/MS): 389.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2Cl)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:30]1(B(O)O)[CH2:32][CH2:31]1.C1(C)C=CC=CC=1>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Cl-].[Cl-].[Pd+2].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[CH:30]2[CH2:32][CH2:31]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C2CC2)c1
Yield: 105.4 %

Procedure:
To a mixture of 4-(2-chloro-4-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester (932 mg), bis(tricyclohexylphosphine)palladium (II) dichloride (132 mg), tripotassium phosphate (3.8 g) and cyclopropylboronic acid (688 mg) were added toluene (10 mL) and water (500 μL) and the mixture was refluxed for 5 hr. After cooling, the mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give 4-(2-cyclopropyl-4-methylphenyl)piperazine-1carboxylic acid tert-butyl ester (1 g). 4-(2-Cyclopropyl-4-methylphenyl)piperazine-1carboxylic acid tert-butyl ester (1 g) was dissolved in chloroform (1 mL), 4N hydrogen chloride/ethyl acetate (1 mL) was added, and the mixture was stirred at room temperature for 3 hr. Filtration gave 1-(2-cyclopropyl-4-methylphenyl)piperazine hydrochloride (160 mg). To tetrahydrofuran (2 mL) were added 4-iodobenzoyl chloride (169 mg), 1-(2-cyclopropyl-4-methylphenyl)piperazine hydrochloride (160 mg) and 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature overnight. Ethyl acetate was added for partitioning, the organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give the title compound (280 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[CH:27])=[CH:22][CH:21]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:27]#[C:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: C#Cc1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(Cl)cc2)cc1[N+](=O)[O-]
Yield: 88.3 %

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) (728 mg, 2.0 mmol) and 4-chlorophenylacetylene (416 mg, 3.0 mmol) according to the general procedure F. Obtained as a yellow solid (658 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=1
Reactant: Cc1sc2nc(-c3ccccn3)nc(Cl)c2c1Cl
Reactant: NCc1ccc(F)cc1
Product: Cc1sc2nc(-c3ccccn3)nc(NCc3ccc(F)cc3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-2-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(4-fluorobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1([C:15](OCC)=[O:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Li+].[BH4-]>C1COCC1.C(O)C.O>[OH:16][CH2:15][C:2]1([CH3:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a mixture of 1-tert-butyl 4-ethyl 4-methylpiperidine-1,4-dicarboxylate (0.10 g, 0.37 mmol) in THF (10 mL) and ethanol (20 mL) was added LiBH4 (0.032 g, 1.5 mmol). The mixture was stirred for about 8 h at rt. The mixture was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The EtOAc extracts were combined, dried over anhydrous Na2SO4, and concentrated in vacuo to give tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate (0.067 g, 80%): LC/MS (Table 2, Method i) Rt=0.29 min; MS m/z: 130 (M-Boc+H)+.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH:35]([CH3:37])[CH3:36])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[N:8]=1)=[O:6].C(OC1C(=O)N=C(CC2C=CC=C(Cl)C=2Cl)N2CCN(C(C)C)C(=O)C=12)C1C=CC=CC=1>>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=2)[N:8]2[CH2:2][CH2:3][N:4]([CH:35]([CH3:37])[CH3:36])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)N(CCO)C(=O)c1nc(Cc2ccccc2-c2ccncc2)nc(O)c1OCc1ccccc1
Agent: CC(C)N1CCn2c(Cc3cccc(Cl)c3Cl)nc(=O)c(OCc3ccccc3)c2C1=O
Product: CC(C)N1CCn2c(Cc3ccccc3-c3ccncc3)nc(=O)c(OCc3ccccc3)c2C1=O
Yield: 19.2 %

Procedure:
9-Benzyloxy-2-isopropyl-6-(2-pyridin-4-yl-benzyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (153) (83 mg, 57.73%) as an off-white solid was synthesized from 5-benzyloxy-6-hydroxy-2-(2-pyridin-4-yl-benzyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (152) (150 mg, 0.90 mmol) following the procedure as described for 9-benzyloxy-6-(2,3-dichlorobenzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (134).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]3[NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:25])[CH3:26])=[CH:19][CH:18]=2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN(C)C)cc1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(CN(C)C)cc1
Yield: 62.1 %

Procedure:
Following general procedure M, 1-(6-bromo-4-((4-((dimethylamino)methyl)phenyl)amino)quinolin-3-yl)propan-1-one (125 mg, 0.30 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (91 mg, 0.33 mmol) to afford the desired product (89 mg, 62%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.02 (s, 1H), 8.09-7.88 (m, 3H), 7.35-7.18 (m, 4H), 7.16-7.09 (m, 2H), 3.42 (s, 2H), 3.09 (q, J=7.1 Hz, 2H), 2.14 (s, 6H), 0.98 (t, J=7.1 Hz, 3H). APCI MS m/z 478 [C27H25ClFN3O2+H]+; HPLC>99% (AUC), tR=8.10 min.
Reaction SMILES: [C@H:1]12[CH2:23][C@H:4]([N:5]([C:7]([C:9]3[N:13]4[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:17](Br)[C:12]4=[N:11][CH:10]=3)=[O:8])[CH2:6]1)[CH2:3][O:2]2.C1(C(C2C=CC=CC=2)=[NH:31])C=CC=CC=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+]>O1CCOCC1.[Cl-].[NH4+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:31][C:17]1[C:12]2[N:13]([C:9]([C:7]([N:5]3[CH2:6][C@@H:1]4[CH2:23][C@H:4]3[CH2:3][O:2]4)=[O:8])=[CH:10][N:11]=2)[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=1
Reactant: O=C(c1cnc2c(Br)cc(C(F)(F)F)cn12)N1C[C@@H]2C[C@H]1CO2
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Nc1cc(C(F)(F)F)cn2c(C(=O)N3C[C@@H]4C[C@H]3CO4)cnc12
Temperature: 120 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A mixture of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl(8-bromo-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)methanone (300 mg), 1,1-diphenylmethanimine (209 mg), tris(dibenzylideneacetone)dipalladium(0) (17.6 mg), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (44.5 mg) and sodium tert-butoxide (111 mg) in 1,4-dioxane (4.0 mL) was stirred with microwave irradiation at 120° C. for 60 min. The reaction mixture was diluted with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was diluted with THF, 1N hydrochloric acid was added thereto, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (207 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([CH3:7])([SH:6])[CH3:5].[H-].[Na+].F[C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:13][CH:12]=1>CN(C)C=O.O>[NH2:2][CH2:3][C:4]([S:6][C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[CH:13][CH:12]=1)([CH3:7])[CH3:5]
Reactant: CC(C)(S)CN
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(SC(C)(C)CN)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a suspension of 1-amino-2-methyl-2-propanethiol hydrochloride (75 mg) in N,N-dimethylformamide (2 mL) is added sodium hydride (60% dispersion in mineral oil, 50 mg) and the mixture is stirred at room temperature for 30 minutes. To the mixture is added tert-butyl 4-fluorobenzoate (50 mg) and the mixture is stirred at 70° C. for 4 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is concentrated in vacuo and the resultant product is purified by flash column chromatography on NH-silica gel (solvent; ethyl acetate) to give tert-butyl 4-[(2-amino-1,1-dimethylethyl)thio]benzoate (54 mg, yield; 75%) as a colorless oil. MS (APCI) m/z: 282 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]2[C:9]([C:10]=1[CH:11](O)[C:12]([NH2:14])=[O:13])=[CH:8][C:7]([N+:16]([O-:18])=[O:17])=[CH:6][CH:5]=2.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][C:2]1[N:3]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([NH2:14])=[O:13])=[CH:8][C:7]([N+:16]([O-:18])=[O:17])=[CH:6][CH:5]=2
Reactant: Cc1c(C(O)C(N)=O)c2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(CC(N)=O)c2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Reaction time: 1 h
Yield: 52.1 %

Procedure:
A solution of 0.927 g (2.7 mmol) of 2-methyl-5-nitro-1-(phenylmethyl)-1H-indole-3-glycolic acid amide in 15 mL of trifluoroacetic acid was treated with 1.0 mL (6.0 mmol) of triethylsilane and the mixture stirred for 1.0 hour. After concentrating at reduced pressure, the residue was chromatographed on silca (eluted with EtOAc) and crystallized from MeOH/CH2Cl2 to give 455 mg (52% yield) of 2-methyl-5-nitro-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 189°-192° C.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][NH:7][C:8]([NH:10][CH:11]1[CH2:13][CH2:12]1)=[O:9])=O.Cl>[OH-].[Na+]>[CH:11]1([N:10]2[C:4]([C:3]3[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=3[F:1])=[N:6][NH:7][C:8]2=[O:9])[CH2:13][CH2:12]1
Reactant: O=C(NNC(=O)c1ccccc1F)NC1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]nc(-c2ccccc2F)n1C1CC1

Procedure:
0.89 g (3.75 mmol) of 2-(2-fluorobenzoyl)-N-cyclopropylhydrazinecarboxamide from Example 3A are heated under reflux in 3.75 ml 2 N aqueous sodium hydroxide for about 45 hrs. To complete the reaction, a further 5 ml 6 N aqueous sodium hydroxide are added and the mixture heated once more under reflux for 6 hrs. After cooling, it is acidified with 1 N hydrochloric acid with stirring and the reaction mixture extracted three times with ethyl acetate. The combined organic phases are dried over magnesium sulphate and concentrated. 0.74 g (73% of theory) of the target compound are thus obtained, which is further reacted without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=1>C(OCC)(=O)C.[Pd]>[CH3:2][C:3]1[O:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(CCl)o1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)o1
Yield: 94 %

Procedure:
A solution of methyl 5-chloromethyl-2-furoate (5.0g, 28.7mmol) in ethyl acetate (40ml) was hydrogenated over 10% palladium on charcoal (50mg) for 3h. The catalyst was filtered off and washed with ethyl acetate. The combined filtrates were concentrated in vacuo and the residue purified by chromatography on silica gel eluting with 10% ethyl acetate in hexane to yield the title compound as a colourless oil (3.78g, 94%); vmax (CH2Cl2) 1725, 1534, 1522, 1437 and 1311cm-1 ; δH (CDCl3, 90MHz) 2.38 (3H, s), 3.86 (3H, s), 6.12 (1H, br d, J 4Hz) and 7.07 (1H, d, J 4Hz). [Mass spectrum: M+(140)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:21]1[CH2:35][C@H:34]([OH:36])[CH2:33][C@H:22]1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20].[CH3:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[C:41]([O:49][C:50]([F:53])([F:52])[F:51])[CH:40]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:45]([C:42]1[CH:43]=[CH:44][C:39]([O:38][CH3:37])=[CH:40][C:41]=1[O:49][C:50]([F:51])([F:52])[F:53])(=[O:47])=[O:46])[C:6](=[O:11])[C:5]2([N:21]1[CH2:35][C@H:34]([OH:36])[CH2:33][C@H:22]1[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20]
Reactant: COc1ccc(C)cc1C1(N2C[C@H](O)C[C@H]2C(=O)OCc2ccccc2)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)OCc3ccccc3)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 71.7 %

Procedure:
With 2.6 g of the compound obtained in Step 157-3 (Isomer B) and 1.79 g of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 2.8 g of the title compound (colorless amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1.[O:11]1[C:15]2([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1>CCOCC>[CH3:9][N:8]([CH3:10])[C:5]1[N:6]=[CH:7][C:2]([C:18]2([OH:21])[CH2:19][CH2:20][C:15]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:16][CH2:17]2)=[CH:3][CH:4]=1
Reactant: CN(C)c1ccc(Br)cn1
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: CCOCC
Product: CN(C)c1ccc(C2(O)CCC3(CC2)OCCO3)cn1

Procedure:
The title compound was prepared as a white solid from 5-bromo-2-dimethylamino-pyridine (Indofine) and 1,4-dioxa-spiro[4.5]decan-8-one in ether using the procedure described in Step A of Example 1.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:26])([F:25])[C:8]1[N:12]2[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][CH:20]([CH2:23][OH:24])[CH2:19][CH2:18]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:24][CH2:23][CH:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:15]=[CH:16][C:11]3[N:12]([C:8]([C:7]([F:6])([F:25])[F:26])=[N:9][N:10]=3)[N:13]=2)[CH2:18][CH2:19]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Reaction time: 0.33 h
Yield: 60.4 %

Procedure:
Methanesulfonyl chloride (2.83 mL, 36.51 mmol) in DCM (30 mL) was added dropwise to a stirred partial solution of [1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]methanol (10 g, 33.19 mmol) and triethylamine (5.09 mL, 36.51 mmol) in DCM (140 mL). The reaction was stirred for 20 minutes, quenched with water (100 mL) and extracted with DCM (2×75 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford a yellow solid. The crude solid was triturated with ether to give a solid which was collected by filtration and dried under vacuum to give 6-[4-(methanesulfonyloxymethyl)piperidin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (7.60 g, 60.4%) as a white solid.