Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>C1(C)C=CC=CC=1>[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:27]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1cccc(Cl)c1
Yield: 81.7 %

Procedure:
0.5 g (0.0026 mol) of 1-benzyl-4-hydroxypiperidine and 0.64 ml (0.0046 mol) of triethylamine were dissolved in 20 ml of toluene and treated with 0.27 ml (0.0021 mol) of 3-chloro-benzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.566 g (82%) of 1-benzyl-piperidin-4-yl 3-chloro-benzoate was obtained as a yellow oil. MS: mele (% basic peak)=329 (C19H20CINO2+, 10), 252 (10), 173 (35), 139 (15), 91 (100), 82 (100).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:22])=[C:18](/[F:21])\[CH2:19][OH:20])[C:3]=1[O:23][CH2:24][CH3:25].C[N+]1([O-])CCOCC1.ClCCl>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:22])=[C:18](/[F:21])\[CH:19]=[O:20])[C:3]=1[O:23][CH2:24][CH3:25]
Reactant: CCOc1c(/C(C)=C(/F)CO)cc2c(c1Cl)C(C)(C)CC=C2C(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CCOc1c(/C(C)=C(/F)C=O)cc2c(c1Cl)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure H-1, (2E)-3-(4-chloro-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)-2-fluoro-but-2-en-1-ol (Compound A-144, 0.18 g, 0.49 mmol), tetrapropylammonium perruthenate (25 mg, 0.071 mmol) and 4-methylmorpholine N-oxide (115 mg, 0.98 mmol) were reacted in acetonitrile and dichloromethane to give the title compound after purification by flash column chromatography (silica gel, 10% ethyl acetate in hexanes).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[C:5]([C:7]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:8]=1[C:9](O)=[O:10])=O.O.[NH2:25][NH2:26]>>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[C:5]1[C:7]2[C:8](=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[C:9](=[O:10])[NH:26][N:25]=1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2C(=O)O)c(OC)c1
Reactant: NN
Solvent: O
Product: COc1ccc(-c2n[nH]c(=O)c3cc(OC)ccc23)c(OC)c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting 2-(2,4-dimethoxybenzoyl)-5-methoxybenzoic acid with hydrazine hydrate.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7](=[O:11])[CH2:8][C:9]#[N:10])=[O:5])[CH3:2].[C:12](OCC)(OCC)([O:14][CH2:15][CH3:16])[CH3:13].C(OC(=O)C)(=O)C>>[C:9]([C:8](=[C:12]([O:14][CH2:15][CH3:16])[CH3:13])[C:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:11])#[N:10]
Reactant: CCOC(C)(OCC)OCC
Reactant: CCOC(=O)NC(=O)CC#N
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)NC(=O)C(C#N)=C(C)OCC

Procedure:
Following the method of Example 1, N-ethoxycarbonylcyanoacetamide is heated with triethyl orthoacetate and acetic anhydride to give α-cyano-β-ethoxy-β-methyl-N-ethoxycarbonylacrylamide, which in turn is reacted with 2,4,6-trichlorophenylhydrazine. The resulting compound α-cyano-β-methyl-β-(2,4,6-trichlorophenylhydrazino)-N-ethoxycarbonylacrylamide (m.p.=183°-184°) is cyclized, yielding 5-cyano-6-methyl-1-(2,4,6-trichloroanilino)-2,4-pyrimidinedione, m.p.=>305°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[N:7][O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.[CH3:21][O:22][C:23]([C:25]1[C:30]([Cl:31])=[N:29][C:28](Cl)=[C:27]([Cl:33])[N:26]=1)=[O:24].C(N(C(C)C)CC)(C)C>CS(C)=O.C([O-])(O)=O.[Na+]>[CH3:21][O:22][C:23]([C:25]1[C:30]([Cl:31])=[N:29][C:28]([N:1]2[CH2:2][CH2:3][C:4](=[N:7][O:8][CH:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]3)[CH2:5][CH2:6]2)=[C:27]([Cl:33])[N:26]=1)=[O:24]
Reactant: COC(=O)c1nc(Cl)c(Cl)nc1Cl
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCNCC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1nc(Cl)c(N2CCC(=NOC3CCN(C(=O)OC(C)C)CC3)CC2)nc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2d (99 mg, 0.35 mmol), 56a (92 mg, 0.35 mmol) and diisopropylethylamine (0.1 mL, 0.6 mmol) were combined in 0.5 mL of DMSO and stirred at room temperature for 18 h. The mixture was diluted with aqueous NaHCO3 (5 mL) and extracted with EtOAc (5 mL). The organic layer was concentrated under vacuum to afford the crude 56b. 20 mg of this crude material was purified by preparative HPLC to afford 56b: LC-MS 488.3 (MH+).
Reaction SMILES: [F:1][C:2]1([C:21]([OH:23])=O)[CH2:7][CH2:6][N:5]([S:8]([C:11]2[C:12]([C:17]([F:20])([F:19])[F:18])=[N:13][N:14]([CH3:16])[CH:15]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1.[F:24][C:25]([F:35])([F:34])[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>>[F:24][C:25]([F:34])([F:35])[O:26][C:27]1[CH:28]=[CH:29][C:30]([NH:31][C:21]([C:2]2([F:1])[CH2:3][CH2:4][N:5]([S:8]([C:11]3[C:12]([C:17]([F:18])([F:19])[F:20])=[N:13][N:14]([CH3:16])[CH:15]=3)(=[O:9])=[O:10])[CH2:6][CH2:7]2)=[O:23])=[CH:32][CH:33]=1
Reactant: Cn1cc(S(=O)(=O)N2CCC(F)(C(=O)O)CC2)c(C(F)(F)F)n1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Product: Cn1cc(S(=O)(=O)N2CCC(F)(C(=O)Nc3ccc(OC(F)(F)F)cc3)CC2)c(C(F)(F)F)n1
Yield: 15.8 %

Procedure:
This material was made in analogy to example 1 from 4-fluoro-1-(1-methyl-3-trifluoromethyl-1H-pyrazole-4-sulfonyl)-piperidine-4-carboxylic acid (0.176 g) and 4-trifluoromethoxy-aniline (0.087 g) to give the desired 4-fluoro-1-(1-methyl-3-trifluoromethyl-1H-pyrazole-4-sulfonyl)-piperidine-4-carboxylic acid (4-trifluoromethoxy-phenyl)-amide (0.04 g) as a white solid. MS (ESI): 519.28 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([CH:15]=O)[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([CH2:15][NH:24][CH2:23][C:22]3[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(C=O)cc2s1
Reactant: COc1ccc(CN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2ccc(CNCc3ccc(OC)cc3)cc2s1

Procedure:
To a solution of 6-formyl-benzo[b]thiophene-2-carboxylic acid ethyl ester (1.05 g, 4.48 mmol) and 4-methoxy-benzylamine (0.76 mL, 5.86 mmol) in anhydrous dichloroethane (40 mL) were added sodium triacetoxyborohydride (2.87 g, 13.5 mmol) and acetic acid (0.25 mL, 4.4 mmol). After the reaction was complete, the reaction mixture was diluted with 60 mL of CH2Cl2 and 40 mL of saturated NaHCO3. The organic layer was separated, washed with 50 mL of water, 50 mL of brine and then dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was purified by flash column chromatography to give 6-[(4-methoxy-benzylamino)-methyl]-benzo[b]thiophene-2-carboxylic acid ethyl ester as a white solid. MS (EI): cal'd 356.1 (MH+), exp 356.1 (MH+).
Reaction SMILES: C(OCC(C)C)=C.C(Cl)(Cl)=O.[CH2:12]([OH:16])[CH:13]([CH3:15])[CH3:14].C(O[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25])C(C)C>>[CH2:12]([O:16][C:23](=[CH2:22])[C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CO
Reactant: CC(C)COC=CC(=O)OCC(C)C
Agent: C=COCC(C)C
Agent: O=C(Cl)Cl
Product: C=C(OCC(C)C)C(=O)OCC(C)C
Temperature: 52.5 °C

Procedure:
100 g (1.0 mol) of isobutyl vinyl ether are initially charged in a 500 ml stirred apparatus and heated to 50-55° C. 113 g (1.15 mol) of phosgene are subsequently introduced over a period of 11 h. After an extra reaction time of 1.5 h, the reaction mixture is stripped phosgene free at 50-55° C. by introduction of nitrogen. The mixture is subsequently allowed to cool to room temperature, and and [sic] 60.7 g (0.82 mol) of isobutanol are added dropwise. After the addition has ended, the resulting reaction mixture is rectified. This gives 150.4 g (75%) of isobutyl 3-isobutoxyacrylate of b.p. 97° C. at 2.5 mbar.
Reaction SMILES: S([O-])([O:4][CH2:5][C:6]([N+:14]([O-:16])=[O:15])([N+:11]([O-:13])=[O:12])[CH2:7][N:8]=[N+:9]=[N-:10])(=O)=O.[Na+].S(=O)(=O)(O)O>>[N:8]([CH2:7][C:6]([N+:11]([O-:13])=[O:12])([N+:14]([O-:16])=[O:15])[CH2:5][OH:4])=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=NCC(COS(=O)(=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: [N-]=[N+]=NCC(CO)([N+](=O)[O-])[N+](=O)[O-]

Procedure:
Scheme 3 illustrates the conversion of 2,2-dinitro 1,3-propanediol cyclic sulfate into 3-azido 2,2-dinitropropanol. First, 2,2-dinitro 1,3-propanediol cyclic sulfate is reacted with sodium azide and dimethylformamide (“DMF”) to open the cyclic sulfate and form sodium 3-azido-2,2-dinitropropyl sulfate. After the cyclic sulfate is opened, the sodium 3-azido-2,2-dinitropropyl sulfate is reacted with 20% sulfuric acid to form 3-azido-2,2-dinitropropanol.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O.[NH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>>[NH2:20][C:4]1[N:3]=[C:2]([NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[N:19]=[C:18]2[C:5]=1[N:6]=[CH:7][NH:8]2
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: CC(C)(C)OC(=O)NCCNc1nc(N)c2nc[nH]c2n1
Temperature: 120 °C

Procedure:
To a microwave tube containing 2-chloroadenosine (Aldrich Chemical) is added tert-butyl N-(2-aminoethyl)carbamate (AK Scientific, 10-fold molar excess). The mixture is heated in a microwave for 20 minutes at 120° C. under nitrogen. Workup of the reaction mixture, purification, and isolation of the title intermediate is carried out in a manner similar to that of Example 4, ROUTE 1, Step 3 used for Compound 16A.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][C@H:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[O:17]CC2C=CC=CC=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:25]1[CH2:29][C@H:28]([N:30]2[CH:34]=[C:33]([CH3:35])[CH:32]=[N:31]2)[C@@H:27]([OH:36])[C@H:26]1[OH:37].FC(F)(F)C(O)=O.NC1N=C(N[C@@H]2CCC[C@H]2O)N=C2C=1N=CN2[C@@H]1C[C@H](N2C=C(C)C=N2)[C@@H](O)[C@H]1O>>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][C@H:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[OH:17])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:25]1[CH2:29][C@H:28]([N:30]2[CH:34]=[C:33]([CH3:35])[CH:32]=[N:31]2)[C@@H:27]([OH:36])[C@H:26]1[OH:37]
Reactant: Cc1cnn([C@H]2C[C@@H](n3cnc4c(N)nc(N[C@H]5CCC[C@@H]5OCc5ccccc5)nc43)[C@H](O)[C@@H]2O)c1
Agent: Cc1cnn([C@H]2C[C@@H](n3cnc4c(N)nc(N[C@@H]5CCC[C@H]5O)nc43)[C@H](O)[C@@H]2O)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnn([C@H]2C[C@@H](n3cnc4c(N)nc(N[C@H]5CCC[C@@H]5O)nc43)[C@H](O)[C@@H]2O)c1

Procedure:
The title compound is prepared from (1R,2S,3R,5S)-3-[6-Amino-2-((1S,2S)-2-benzyloxy-cyclopentylamino)-purin-9-yl]-5-(4-methyl-pyrazol-1-yl)-cyclopentane-1,2-diol (Example 23) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-Amino-2-((1R,2R)-2-hydroxy-cyclopentylamino)-purin-9-yl]-5-(4-methyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoroacetate (Example 29). MS (ES+) m/e 415 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][N:23](C)[CH3:24])([C:8](=O)C2C=CC=CC=2)N[CH:7]=1.[N:26]#[C:27]Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:22][N:23]=[C:24]([C:4]3[CH:3]=[CH:2][CH:7]=[CH:27][N:26]=3)[C:8]=2[CH:7]=1
Reactant: N#CBr
Reactant: CN(C)Cc1ccccc1C1(C(=O)c2ccccc2)C=CC(Cl)=CN1
Solvent: ClCCl
Product: Clc1ccc2c(c1)C(c1ccccn1)=NCc1ccccc1-2

Procedure:
The solution of 4.5 g of 5-chloro-2-(o-dimethylaminomethyl-phenyl)-2-benzoylpyridine in 120 ml of methylene chloride is treated during 4 hours with 13.7 ml of 0.94 molar cyanogen bromide in methylene chloride. The mixture is evaporated, the residue dissolved in 200 ml of saturated methanolic ammonia, and the solution evaporated after 2 days. The residue is taken up in aqueous sodium carbonate, the mixture extracted with diethyl ether, the extract washed with saturated aqueous sodium chloride, decolorized with activated charcoal, evaporated and the residue crystallized from diethyl ether to give the 9-chloro-7-(2-pyridyl)-5H-dibenz[c,e]azepine melting at 153°-155°.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:17][CH2:16][CH:15]([O:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.O.NN>C(O)C>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:13][CH2:14][CH:15]([O:18][NH2:19])[CH2:16][CH2:17]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NOC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Yield: 92.5 %

Procedure:
A solution of 2-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yloxy)isoindoline-1,3-dione (4.85 g, 10.0 mmol) and hydrazine monohydrate (550 mg, 11.0 mmol) in ethanol (30 ml) was stirred at room temperature for 30 minutes. The resulting solid was filtered off and concentrated in vacuo. The residue was triturated with diethyl ether (80 ml), and the resulting solid was filtered off again and concentrated in vacuo to give O-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yl)hydroxylamine (3.00 g, 93%) as a white solid: LCMS: 325 [M+1]+.
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][C:27](OCC)=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][C:27]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:20][CH2:19]2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCCN1CCC(c2ccc(OC)cc2)CC1
Reactant: ON=C1CCCCCC1
Product: COc1ccc(C2CCN(CCCc3onc4c3CCCCC4)CC2)cc1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(4-methoxyphenyl)piperidin-1-yl)-n-butyrate, 3-(3-(4-(4-methoxyphenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: C=O.Cl.[Br:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]2[OH:18])=[C:7]([N+:19]([O-:21])=[O:20])[CH:6]=1.[C:22](O)(=O)C.C([BH3-])#N.[Na+]>O>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([CH3:22])[CH2:14][C@@H:13]2[OH:18])=[C:7]([N+:19]([O-:21])=[O:20])[CH:6]=1
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1cc(Br)ccc1N[C@H]1CCNC[C@@H]1O
Agent: C=O
Agent: Cl
Agent: [BH3-]C#N
Solvent: O
Product: CN1CC[C@H](Nc2ccc(Br)cc2[N+](=O)[O-])[C@@H](O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Add formaldehyde (24 mL, 37-41% aqueous solution) to a solution of (3S,4S)-4-(4-bromo-2-nitro-phenylamino)-piperidin-3-ol, hydrochloride (0.028 mol, 9.8 g) and acetic acid (12 mL) in water (46 mL) and stir the reaction mixture at room temperature for 30 min. Add sodium cyanoborohydride (0.083 mol, 5.26 g) and stir the reaction mixture for 3 h. Quench the reaction mixture with sodium bicarbonate solution and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (8.4 g, 92%). 1H NMR (400 MHz, CDCl3) δ 1.63-1.71 (m, 1H), 2.16-2.21 (m, 2H), 2.33 (s, 3H), 2.35-2.38 (m, 1H), 2.60 (br s, 1H), 2.80 (d, 1H), 3.54-3.56 (m, 1H), 3.75-3.79 (m, 1H), 6.92 (d, 1H), 7.48 (dd, 1H), 8.14 (d, 1H), 8.30 (d, 1H).
Reaction SMILES: Br[CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][Cl:6].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:6][CH2:5][C:4]([CH3:8])([CH3:7])[C:3](=[O:9])[CH2:2][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)=[CH:22][CH:21]=1
Reactant: CC(C)(CCl)C(=O)CBr
Reactant: Oc1ccc(-c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(CCl)C(=O)COc1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 15 h
Yield: 55.6 %

Procedure:
42.7 g (0.2 mol) of 1-bromo-4-chloro-3,3-dimethyl-butan-2-one were added dropwise to a boiling suspension of 41 g (0.2 mol) of 4-(4-chlorophenyl)-phenol and 28 g (0.2 mol) of potassium carbonate in 300 ml of absolute acetone. The mixture was stirred for 15 hours under reflux and was then allowed to cool and the inorganic residue was filtered off and rinsed with acetone. The filtrate was concentrated by distilling off the solvent in vacuo. The residue crystallized after the addition of 50 ml of diisopropyl ether. 37.5 g (55% of theory) of 4-chloro-1-[4-(4-chlorophenyl)-phenoxy]-3,3-dimethyl-butan-2-one of melting point 67°-68° C. were obtained.
Reaction SMILES: [O-][CH2:2]C.[Na+].[CH3:5][O:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][C:14]2[C:15](=[O:21])[NH:16][C:17](=[S:20])[NH:18][CH:19]=2)=[CH:9][N:8]=1.CI>CCO>[CH3:5][O:6][C:7]1[N:8]=[CH:9][C:10]([CH2:13][C:14]2[C:15](=[O:21])[N:16]=[C:17]([S:20][CH3:2])[NH:18][CH:19]=2)=[CH:11][N:12]=1
Reactant: COc1ncc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: COc1ncc(Cc2c[nH]c(SC)nc2=O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
Into a stirred solution of sodium ethoxide (1.358 mmol, 2 eq) in EtOH (3 ml) was added 5-(2-methoxy-pyrimidin-5-ylmethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.679 mmol, 1 eq) at rt. After 30 min, the reaction mixture was treated with methyl iodide (1.358 mmol, 2 eq) and was stirred at rt overnight. Solvent was evaporated and a crude product was purified on Biotage SP1 Snap Si 10; 15 ml/min in the gradient of EtOAc in Cyclohexane: 0-10% in 30 CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 5-(2-methoxy-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (0.568 mmol, yield=83%, purity=46%). [M+H]+=265.25 1H NMR (300 MHz, DMSO-d6) δ/ppm 2.39 (s, 1H), 3.82-3.87 (m, 3H), 7.75 (s, 1H), 8.47 (s, 2H)
Reaction SMILES: [CH3:1][CH:2]([O:4]C(/N=N/C(OC(C)C)=O)=O)C.[F:15][C:16]([F:40])([F:39])[C:17]1[N:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]4[CH:33]=[C:34]([OH:38])[CH:35]=[CH:36][CH:37]=4)[CH2:28][CH2:27]3)[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCCC1OCCO>C1COCC1>[F:40][C:16]([F:15])([F:39])[C:17]1[N:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]4[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=4)[O:38][CH2:1][CH2:2][OH:4])[CH2:28][CH2:27]3)[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Reactant: Oc1cccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1
Agent: OCCOC1CCCCO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: OCCOc1cccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.4 %

Procedure:
DIAD (0.081 mL, 0.41 mmol) was added dropwise to 3-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenol (obtained as described in Example 670, preparation of starting materials) (125 mg, 0.34 mmol), triphenylphosphine (108 mg, 0.41 mmol) and 2-(tetrahydro-2H-pyran-2-yloxy)ethanol (60.4 mg, 0.41 mmol) in THF (3 mL) under nitrogen. The resulting mixture was stirred at ambient temperature for 4 hours, then added to an SCX column. The crude product was eluted from the column using 2M ammonia in methanol and the solvents were evaporated. The crude product was purified by flash silica chromatography, elution gradient 80 to 100% EtOAc in isohexane. Fractions containing product were evaporated then further purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-(3-(1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)ethanol (74 mg, 53%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][C:5](=[O:7])[CH3:6].C[O-].[Na+].Br[CH2:13][C:14]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[O:24][CH3:25])=[O:15]>C1COCC1>[CH3:1][O:2][C:3](=[O:8])[CH:4]([CH2:13][C:14]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[O:24][CH3:25])=[O:15])[C:5](=[O:7])[CH3:6]
Reactant: COC(=O)CC(C)=O
Reactant: COc1ccc(OC)c(C(=O)CBr)c1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(CC(=O)c1cc(OC)ccc1OC)C(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
To a solution of 3 g of 3-oxo-butyric acid methyl ester in THF (60 ml) and 5.2 ml of a solution of sodium methoxide (5.4 M in methanol) was added over 15 minutes a solution of 7 g of 2-bromo-1-(2,5-dimethoxy-phenyl)-ethanone in 30 ml of THF. The reaction mixture was allowed to stir at room temperature for 16 hours, during which time a precipitation occurred. The reaction mixture was then diluted in diethyl ether and washed several times with water. The organic phase was then dried with sodium sulfate and concentrated in vacuo. The residue was then triturated with isopropyl ether and filtered to give 6.3 g of the title compound. MS (ISP) 295.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:21]([O-])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)=[N:7][CH:6]=[CH:5]2.O.O.[Sn](Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CCO>[NH2:21][C:3]1[C:2]([CH3:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[C:8]2[NH:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1
Reactant: Cc1ccc2c(Nc3ccc(C#N)cc3)nccc2c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(Nc3ccc(C#N)cc3)nccc2c1N
Temperature: 70 °C
Reaction time: 17 h
Yield: 70.5 %

Procedure:
A mixture of 4-(6-methyl-5-nitroisoquinolin-1-ylamino)benzonitrile (0.47 g, 1.5 mmol), tin(II) chloride dihydrate (1.8 g, 7.7 mmol) and absolute EtOH (50 mL) was stirred under N2 at 70° C. for 17 h. The crude reaction mixture was poured onto ˜100 mL ice. The resulting solution was treated with solid Na2CO3 to pH 10. The milky yellow suspension was extracted with EtOAc (3×150 mL). The combined EtOAc extracts were washed with saturated NaCl (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to give 510 mg as a red solid. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 1% to 5% MeOH in CH2Cl2, to provide 4-(5-amino-6-methylisoquinolin-1-ylamino)benzonitrile (0.29 g, 68% yield) as a red solid. MS (ESI, pos. ion) m/z: 275 [M+H]+.